tag:blogger.com,1999:blog-66846019062126723042024-02-19T18:14:51.950-08:00OSTEOMIELITE CRONICA MULTIFOCALE RICORRENTEAnonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.comBlogger52125tag:blogger.com,1999:blog-6684601906212672304.post-5759613737035628382015-12-19T08:15:00.002-08:002015-12-19T08:15:06.239-08:00QUESTO LO TROVO MOLTO INTERESSANTE<br />
<br />
http://www.medpagetoday.com/Rheumatology/GeneralRheumatology/49453<br />
<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-26579444012136986782014-07-14T05:18:00.001-07:002014-07-14T08:50:31.602-07:00<br />
Questa iniziativa mi piace moltissimo<br />
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<br />
<a href="https://www.booster.com/crmoawareness?share=4621404728522564">https://www.booster.com/crmoawareness?share=4621404728522564</a><br />
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<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-20461418255952736852014-05-09T09:02:00.001-07:002014-05-09T09:02:15.084-07:00IMPORTANTE<br />
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Comunicato stampa Roma, 9 maggio 2014 Cittadinanzattiva-Tribunale per i diritti del malato su Decreto in materia di off label:il diritto alla sicurezza delle cure sacrificato in nome del risparmio “In sole 12 righe l’articolo sull'impiego dei farmaci off label introduce il principio per cui il SSN è autorizzato a risparmiare sacrificando il diritto delle persone alla sicurezza delle cure”, questo il commento di Tonino Aceti, coordinatore nazionale del Tribunale per i diritti del malato-Cittadinanzattiva, sul Decreto n.36 del 20 marzo 2014, in materia di droghe e farmaci off label, già approvato alla Camera e che ieri ha ricevuto parere favorevole dalle Commissioni Giustizia e Sanità del Senato.Il Decreto infatti prevede la possibilità per il SSN, anche in presenza di una valida alternativa terapeutica espressamente autorizzata, di utilizzare terapie fuori indicazione terapeutica la cui efficacia e sicurezza non è testata dalle fasi di sperimentazione clinica previste dalla Legge, ma è affidata soltanto a “ricerche nazionali o internazionali” la cui robustezza e affidabilità non sono ancora chiare ai cittadini.“Il Decreto andrebbe ritirato o modificato sostanzialmente nella parte relativa all'impiego degli off label: si corre il rischio, infatti, di non avere più diritto alla cura migliore per le specificità della persona, ma il criterio guida è il minor costo e non c’è garanzia che il cittadino ne sia informato o possa scegliere insieme al medico. Inoltre le evidenze delle sperimentazioni cliniche potrebbero non essere più indispensabili e le responsabilità legali legate all'eventuale danno per la salute dei cittadini saranno in capo al SSN”.“Siamo convinti che le risorse economiche a disposizione debbano essere utilizzate al meglio - conclude Aceti - e che si possa e si debba farlo rispettando tutti i diritti dei cittadini, attraverso ad esempio nuove politiche condivise e partecipate di negoziazione dei prezzi delle terapie”.Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-13567566253865584632014-05-06T09:48:00.001-07:002014-05-06T09:48:36.117-07:00Una amica americana con CRMO mi ha mandato un link molto interessante.<br />
Vi consiglio vivamente di leggerlo<br />
Questo è il titolo<br />
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<span style="font-family: 'AdvPA0C4'; font-size: 19.000000pt;">Homozygous mutations in </span><span style="font-family: 'AdvPA0C7'; font-size: 19.000000pt;">LPIN2 </span><span style="font-family: 'AdvPA0C4'; font-size: 19.000000pt;">are responsible for the
syndrome of chronic recurrent multifocal osteomyelitis and
congenital dyserythropoietic anaemia (Majeed syndrome) </span><br />
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E questo è il link<br />
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736104/pdf/v042p00551.pdf">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736104/pdf/v042p00551.pdf</a>Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-7213474992677078592014-05-05T01:59:00.002-07:002014-05-05T01:59:28.375-07:00In questi giorni ho sentito spesso parlare di CRMO associata alla mutazione del gene LIPIN2<br />
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Posto due link interessanti. Se qualcuno ha altre notizie lo invito a postarle.<br />
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<a href="http://www.ncbi.nlm.nih.gov/pmc/article/PMC3726202">http://www.ncbi.nlm.nih.gov/pmc/article/PMC3726202</a><br />
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<span style="background-color: rgba(255, 255, 255, 0);"><a href="http://www.ncbi.nlm.nih.gov/m/pubmed/17496555">http://www.ncbi.nlm.nih.gov/m/pubmed/17496555</a></span><br />
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<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-11465183516863009322014-04-17T06:24:00.001-07:002014-07-14T08:48:56.225-07:00
<a href="http://www.aboutkidshealth.ca/En/HealthAZ/ConditionsandDiseases/InflammatoryConditions/Pages/Chronic-Recurrent-Multifocal-Osteomyelitis-CRMO.aspx"></a>Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-268693575054016332014-04-04T06:29:00.000-07:002014-04-04T06:29:00.860-07:00REGISTRO NAZIONALE MALATTIE RARE
Il Registro Nazionale Malattie Rare è istituito presso l’ISS in attuazione dell’articolo 3 del D.M. 279/2001.
Il Registro ha come obiettivi generali di effettuare la sorveglianza delle malattie rare e di supportare la programmazione nazionale e regionale degli interventi per i soggetti affetti da malattie rare (art .3).
Il Registro mira infatti ad ottenere informazioni epidemiologiche (in primo luogo il numero di casi di una determinata malattia rara e relativa distribuzione sul territorio nazionale) utili a definire le dimensioni del problema; si tratta, inoltre, di uno strumento utile per stimare il ritardo diagnostico e la migrazione sanitaria dei pazienti, supportare la ricerca clinica e promuovere il confronto tra operatori sanitari per la definizione di criteri diagnostici.
L’attività del RNMR è iniziata nel 2001 e, per aumentare la copertura e l’efficienza della raccolta dei dati epidemiologici il Centro Nazionale Malattie Rare (CNMR), a partire dall’inizio del 2007, ha messo in atto una nuova modalità di raccolta dati che include un nuovo software; uno strumento che può essere utilizzato sia dai singoli presidi/centri abilitati alla diagnosi e al trattamento dei pazienti affetti da malattie rare sia dai Responsabili dei Centri di Coordinamento Regionale che coordinano le attività e fanno da tramite tra il CNMR e i singoli presidi/centri.
Il software è sviluppato su piattaforma web, di semplice utilizzo, realizzato rispettando gli standard di sicurezza e di riservatezza per il trattamento dei dati sensibili.
Il CNMR mette a disposizione il software gratuitamente sia alle Regioni che non hanno ancora attivato un proprio Registro Regionale, sia a quelle che ne sono già in possesso.
Il software permette al RNMR di ricevere i dati da ciascun Responsabile del Centro di Coordinamento per la raccolta dei dati epidemiologici.
Con tutte le Regioni è stato condiviso e concordato all’interno dell’Accordo Stato-Regioni del 10 maggio 2007 un elenco di variabili obbligatorie (data set minimo) da inviare al Registro Nazionale Malattie Rare. Il data set minimo prevede campi obbligatori sia per la parte anagrafica di arruolamento del paziente sia per la parte relativa alla patologia; nella sezione facoltativa del Registro Nazionale Malattie Rare è possibile specificare i criteri diagnostici, gli esami clinici, di laboratorio e strumentali alla diagnosi e al follow-up ed è possibile segnalare il decesso del paziente.
L’Accordo Stato-Regioni del 10 maggio 2007 stabilisce anche che le Regioni hanno l’impegno di attivare registri regionali o interregionali sulle malattie rare entro il 31 marzo 2008 e di garantire il collegamento con il RNMR.
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-26616547235336898392014-04-04T04:23:00.001-07:002014-04-04T04:45:50.715-07:00Accesso ai farmaci essenziali per i malati rari1. Classi di rimborso dei farmaci per il Servizio Sanitario Nazionale
Il Prontuario Terapeutico Nazionale comprende la lista dei medicinali in commercio in Italia. Ai fini della rimborsabilità a carico del Servizio Sanitario Nazionale (SSN), i farmaci sono suddivisi in fascia A, fascia H e fascia C.
La classe A comprende farmaci essenziali, destinati alla cura di malattie croniche, interamente rimborsati dal SSN per le indicazioni terapeutiche autorizzate.
I farmaci in classe A con nota limitativa Aifa sono erogabili a totale carico del SSN solo per le specifiche condizioni patologiche o terapeutiche contenute nella nota, le rimanenti indicazioni terapeutiche sono a carico del cittadino. La modalità di fornitura di questi farmaci avviene attraverso le farmacie territoriali o strutture sanitarie pubbliche (distribuzione diretta).
La classe H comprende i farmaci rimborsati dal SSN a condizione che siano utilizzati esclusivamente in ambito ospedaliero o in struttura ad esso assimilabile. Si tratta infatti di medicinali che, per caratteristiche farmacologiche, per modalità di somministrazione, per innovatività o per altri motivi di salute pubblica sono somministrabili negli ospedali o negli ambulatori specialisti.
La classe C comprende farmaci che sono a totale carico del cittadino, in quanto non considerati essenziali o “salvavita”, utilizzati per patologie di lieve entità o minori o, comunque, aventi delle alternative terapeutiche nel Prontuario Farmaceutico Nazionale.
Una categoria farmacologica di largo uso per i pazienti con malattia rara sono i farmaci di fascia C, talvolta essenziali per trattare la malattia rara, le sue complicanze o le sue manifestazioni sintomatologiche: non sono inclusi nei Livelli Essenziali di Assistenza (LEA), ma possono rappresentare per alcuni pazienti le uniche opzioni terapeutiche disponibili e/o possibili. E’ comunque compito esclusivo dei Centri di Riferimento per le malattie rare, individuati dalle Regioni come previsto dal DM 279/2001, definire attraverso un piano assistenziale il trattamento necessario del paziente, anche in relazione alle condizioni specifiche del paziente.
Alcune Regioni hanno emanato disposizioni a riguardo, individuando per gruppi di malattia rara i trattamenti extra-LEA essenziali ed insostituibili da dare gratuitamente ai pazienti che li necessitano, secondo una organizzazione definita.
2. Farmaci off-label
Si definisce "off-label" un farmaco impiegato per indicazioni terapeutiche e modalità di utilizzo (per età, posologia, via di somministrazione) diverse da quelle previste dalla autorizzazione all’immissione in commercio (AIC) rilasciata dall’autorità regolatoria competente.
La prescrizione di un farmaco al di fuori delle indicazioni autorizzate per uso personalizzato e individuale è normata dalla Legge 8 aprile 1998, n. 94 (“Legge Di Bella”). Questa legge consente la prescrizione off-label dei farmaci in casi singoli e ha particolari condizioni: in assenza di valide alternative terapeutiche e se l’impiego del medicinale proposto è e conforme a lavori apparsi su pubblicazioni scientifiche accreditate in campo internazionale. L’uso off-label di un farmaco deve essere effettuato sotto la diretta responsabilità del medico prescrittore e necessita di uno stretto monitoraggio a livello specialistico del paziente, e deve essere preceduto da una adeguata informazione al paziente sui rischi e benefici del trattamento nonché dall’acquisizione del consenso informato dello stesso, a causa della incompletezza dei dati relativi alla sicurezza ed efficacia del farmaco per l’indicazione terapeutica proposta.
La norma suddetta non riconosce il diritto del paziente all’erogazione dei medicinali a carico del SSN.
3. Farmaci della Legge 648/96
La Legge 648/96 prevede l’istituzione di un elenco di medicinali erogabili a totale carico del SSN, qualora non esista valida alternativa terapeutica, che include:
- medicinali innovativi la cui commercializzazione è autorizzata all’estero ma non sul territorio nazionale;
- medicinali non ancora autorizzati ma sottoposti a sperimentazione clinica di cui siano disponibili risultati di studi clinici di Fase II;
- medicinali da impiegare per una indicazione terapeutica diversa da quella autorizzata (usi off-label)
L’elenco dei medicinali e delle relative indicazioni di utilizzo, è predisposto e periodicamente aggiornato dall’AIFA (Agenzia Italiana del Farmaco).
La prescrizione dei farmaci inseriti nel suddetto elenco deve essere effettuata nel rispetto delle condizioni prescrittive previste dal provvedimento CUF 20 luglio 2000, sulla base di un piano terapeutico predisposto dal Centro prescrittore. E’ necessario acquisire il consenso informato scritto del paziente dal quale risulti che lo stesso è consapevole della incompletezza dei dati relativi alla sicurezza ed efficacia del medicinale per l’indicazione terapeutica proposta.
4. L'uso compassionevole dei medicinali
L’accesso ad un medicinale sperimentale al di fuori di uno studio clinico e prima dell’approvazione alla commercializzazione da parte dell’autorità regolatoria competente, viene comunemente definito “uso compassionevole”. In Italia l’uso compassionevole è regolamentato dal DM 8 maggio 2003.
Un medicinale prodotto in uno stabilimento farmaceutico, sottoposto a sperimentazione clinica in Italia o all’estero, può essere richiesto alla ditta produttrice per uso al di fuori della sperimentazione clinica quando non esista valida alternativa terapeutica al trattamento di patologie gravi o di malattie rare o di condizioni di malattia che pongono il paziente in pericolo di vita.
L’autorizzazione all’uso del medicinale può essere rilasciata solo nei seguenti casi:
- medicinale che per la medesima indicazione sia già oggetto di studi clinici, in corso o conclusi, di Fase III o, in caso di condizioni che pongano il paziente in pericolo di vita, di Fase II conclusi;
- i dati disponibili sulle sperimentazioni siano sufficienti per formulare un favorevole giudizio sull’efficacia e tollerabilità del medicinale.
La fornitura può essere richiesta alla ditta produttrice dal medico per un uso su un singolo paziente non incluso nella sperimentazione, o per più pazienti che hanno partecipato alla sperimentazione clinica ottenendo risultati tali, sotto il profilo dell’efficacia e tollerabilità, da configurare la necessità di un tempestivo utilizzo. A seguito della richiesta, la ditta può fornire gratuitamente il farmaco sulla base di un protocollo che deve essere approvato dal Comitato Etico di competenza, che contenga inoltre le modalità di informazione al paziente, ed accompagnato da una nota di assunzione di responsabilità del trattamento secondo protocollo da parte del medico richiedente.
5. Medicinali non in commercio in Italia
Qualora il medico ritenga opportuno sottoporre un proprio paziente ad un trattamento con un medicinale non registrato in Italia ma regolarmente autorizzato in un Paese estero, non sostituibile con altri medicinali in commercio in Italia, è tenuto alla compilazione di una richiesta di importazione del medicinale secondo le indicazioni previste dal DM 11 febbraio 1997, di cui si assume la responsabilità dell’uso e previa acquisizione del consenso informato del paziente. L’importazione è giustificata da oggettivi caratteri di eccezionalità e l’impiego del farmaco deve avvenire nel rispetto, oltre che della normativa in vigore in Italia, delle condizioni di utilizzo autorizzate nel Paese di provenienza. In altre parole, non è possibile importare in Italia un medicinale per indicazioni terapeutiche diverse da quelle autorizzate nel Paese di provenienza.
L’onere della spesa per l’acquisto di medicinali non registrati in Italia è a carico dell’assistito a meno che il farmaco non venga impiegato in ambito ospedaliero.
6. Galenici magistrali
Si definiscono galenici magistrali i medicinali allestiti in farmacia in base ad una prescrizione medica destinata ad un determinato paziente. Il ricorso a tali preparazioni galeniche risponde ad esigenze specifiche del paziente, come la necessità di una terapia personalizzata, o di terapie non reperibili in commercio nelle formulazioni specifiche richieste, attraverso l’allestimento di farmaci “orfani”, ossia in dosaggio o forme farmaceutiche non presenti in commercio.
7. I farmaci orfani
I farmaci “orfani” sono medicinali utilizzati per la diagnosi, la prevenzione ed il trattamento delle malattie rare: si definiscono “orfani” in quanto manca in genere l’interesse da parte delle aziende farmaceutiche ad investire sulla ricerca e sviluppo di un prodotto destinato a pochi pazienti. Le prime normative sui farmaci orfani sono state introdotte negli Stati Uniti con l’entrata in vigore dell’Orphan Drug Act (1983). Nell’Unione Europea, il Regolamento (CE) n. 141/2000 del Parlamento Europeo e del Consiglio del 16 dicembre 1999 definisce anzitutto i criteri per l’assegnazione della qualifica di “orfano” ad un medicinale e la procedura di assegnazione della qualifica. Quando il medicinale è stato designato come orfano da parte del COMP (Committee for Orphan Medicinal Products), istituito in seno all’Agenzia Europea dei Medicinali (EMA), esso viene iscritto nel Registro comunitario dei medicinali orfani. Il Regolamento europeo stabilisce altresì gli incentivi per incoraggiare la ricerca, lo sviluppo e la commercializzazione di questi medicinali: esclusività di mercato di 10 anni, assistenza al protocollo, accesso diretto alla procedura centralizzata per l’autorizzazione all’immissione in commercio, agevolazioni fiscali, priorità all’accesso ai programmi di ricerca europei. Pertanto i farmaci orfani sono approvati a livello centralizzato dall’EMA. La definizione del prezzo e della rimborsabilità sono prerogative nazionali. I farmaci orfani attualmente disponibili nel nostro Paese sono a totale carico del SSN per la loro indicazione terapeutica, quindi completamente rimborsabili nelle condizioni di utilizzo previste dalla loro AIC.
8. I prodotti dietetici per i pazienti con malattie metaboliche congenite
In base al Decreto Ministeriale dell’8 giugno 2001, l’erogazione dei prodotti dietetici destinati ad una alimentazione particolare rientra nei livelli essenziali di assistenza sanitaria per i soggetti con malattie metaboliche congenite accertate e certificate dai Centri di Riferimento individuati dalle Regioni (ed inoltre per i soggetti affetti da fibrosi cistica e malattia celiaca). Il Decreto istituisce il Registro Nazionale dei prodotti destinati ad un'alimentazione particolare, che sono erogati nelle singole regioni a carico del SSN ai pazienti aventi diritto secondo le indicazioni delle modalità organizzative ed erogative scelte dalle regioni.
I prodotti dietetici sono prescrivibili ai pazienti affetti da malattie metaboliche congenite dagli specialisti dei Centri di Riferimento, i quali stabiliscono il regime dietetico appropriato e lo adeguano in relazione alle condizioni cliniche e all’età; si possono ricondurre a due principali categorie di prodotti:
- alimenti speciali come miscele di aminoacidi ed integratori dietetici, destinati al trattamento di specifiche patologie;
- alimenti ipoproteici o aproteici indicati per soggetti affetti da patologie che richiedono un ridotto apporto proteico, ad esempio pasta, pane ed alimenti affini, e dolci ipo/aproteici.
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-1609419219259584312014-03-29T09:06:00.002-07:002014-03-29T09:06:21.008-07:00"il sole 24ore" di domani domenica 23 marzo 2014 - Campagna "Pro Scienza" di UNIAMO F.I.M.R. onlus
Da: RENZA BARBON
Data: Sab, 22 Mar 2014 alle 5:11pm
Comunicato Stampa
Oltre il Metodo Stamina: l’importanza di una sicura ed etica informazione scientifica
Lettera aperta di EURORDIS e UNIAMO FIMR onlus al Ministro della Salute Lorenzin pubblicata su
“Il Sole24Ore” di domenica 23 marzo 2014
UNIAMO F.I.M.R. onlus Federazione Italiana Malattie Rare vive con preoccupazione la persistente mancanza di un dibattito pubblico scientifico sostenuto da una informazione trasparente e di qualità in Italia, entrambi elementi fondamentali perché la persona e/o la famiglia possa esercitare consapevolmente le proprie scelte di cura in un contesto di malattia complessa.
Una apprensione che si ripresenta anche in occasione degli “Stati generali della salute”, promosso e organizzato dal Ministero della Salute per l’8 e 9 aprile 2014, dove, nel Programma dei lavori, l'intento di dare spazio a questa tematica non è ben evidenziato. Eppure questo dovrebbe essere un bisogno centrale non solo nazionale, ma europeo, nel settore dei sistemi sanitari, soprattutto in vista del prossimo semestre di Presidenza italiana dell’Unione Europea, per andare verso una corretta informazione e comunicazione scientifica pubblica.
Per questi motivi UNIAMO F.I.M.R. onlus ha ritenuto opportuno porre all’attenzione dell’opinione pubblica attraverso la pubblicazione su “Il sole24ore” di domenica 23 marzo 2014 la lettera aperta rivolta al Ministro della Salute On.le Beatrice Lorenzin, a firma congiunta UNIAMO F.I.M.R. onlus e EURORDIS European Organization for Rare Disease sulla necessità di un dibattito pubblico informato sulle terapie con cellule staminali e la corretta, sicura ed etica attuazione di trattamenti medici efficaci.
Le recenti vicende legate all’uso e alla sperimentazione del Metodo Stamina hanno rinnovato l’attenzione sull’insostituibile ruolo che ha una sicura ed etica informazione scientifica ed istituzionale nei confronti degli operatori, ma soprattutto dei pazienti, potenziali destinatari delle nuove terapie cellulari: un ulteriore determinante della salute pubblica.
Pur essendo passati diciassette anni dalla firma del Consiglio d’Europa della Convenzione di Oviedo sui diritti dell’uomo e la biomedicina, in Italia, dopo il recepimento della Convenzione con una legge nel 2001, ben poco è stato realizzato di quanto in essa raccomandato.
Sul prevenire queste circostanze negative e rispondere adeguatamente alle domande che gli sviluppi della biologia, della medicina e delle tecnologie bioingegneristiche pongono, la Convenzione raccomandava che i Paesi firmatari avviassero dei dibattiti pubblici appropriati alla luce delle implicazioni mediche, sociali, economiche, etiche e giuridiche pertinenti e che fossero oggetto di consultazioni pubbliche.
Viene chiesto un dibattito pubblico sostenuto da un’informazione trasparente e di qualità per aiutare tutti, ma soprattutto i pazienti e le famiglie a superare il loro isolamento culturale e psicologico e contribuire così alla costruzione di una vera cittadinanza scientifica.Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-80842974509057687322014-03-29T05:40:00.000-07:002014-03-29T05:40:02.445-07:00<div class="article-rel-wrapper">
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);">La lettera aperta di UNIAMO ed EURORDIS al Ministro Lorenzin pubblicata su Il Sole 24 Ore</span></span></h2>
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<span class="createdate" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Sabato 22 Marzo 2014 20:16</span></span></div>
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<em style="background-color: rgba(255, 255, 255, 0);"><em>Lettera aperta di EURORDIS e UNIAMO FIMR onlus al Ministro della Salute Lorenzin pubblicata su "Il Sole24Ore" di domenica 23 marzo 2014</em></em></div>
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<span style="background-color: rgba(255, 255, 255, 0);">UNIAMO F.I.M.R. onlus Federazione Italiana Malattie Rare vive con preoccupazione la persistente mancanza di un dibattito pubblico scientifico sostenuto da una informazione trasparente e di qualità in Italia, entrambi elementi fondamentali perché la persona e/o la famiglia possa esercitare consapevolmente le proprie scelte di cura in un contesto di malattia complessa.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Una apprensione che si ripresenta anche in occasione degli "Stati generali della salute", promosso e organizzato dal Ministero della Salute per l'8 e 9 aprile 2014, dove, nel Programma dei lavori, l'intento di dare spazio a questa tematica non è ben evidenziato. Eppure questo dovrebbe essere un bisogno centrale non solo nazionale, ma europeo, nel settore dei sistemi sanitari, soprattutto in vista del prossimo semestre di Presidenza italiana dell'Unione Europea, per andare verso una corretta informazione e comunicazione scientifica pubblica.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Per questi motivi UNIAMO F.I.M.R. onlus ha ritenuto opportuno porre all'attenzione dell'opinione pubblica attraverso la pubblicazione su "Il sole24ore" di domenica 23 marzo 2014 la lettera aperta rivolta al Ministro della Salute On.le Beatrice Lorenzin, a firma congiunta UNIAMO F.I.M.R. onlus e EURORDIS European Organization for Rare Disease sulla necessità di un dibattito pubblico informato sulle terapie con cellule staminali e la corretta, sicura ed etica attuazione di trattamenti medici efficaci.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Le recenti vicende legate all'uso e alla sperimentazione del Metodo Stamina hanno rinnovato l'attenzione sull'insostituibile ruolo che ha una sicura ed etica informazione scientifica ed istituzionale nei confronti degli operatori, ma soprattutto dei pazienti, potenziali destinatari delle nuove terapie cellulari: un ulteriore determinante della salute pubblica.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Pur essendo passati diciassette anni dalla firma del Consiglio d'Europa della Convenzione di Oviedo sui diritti dell'uomo e la biomedicina, in Italia, dopo il recepimento della Convenzione con una legge nel 2001, ben poco è stato realizzato di quanto in essa raccomandato.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Sul prevenire queste circostanze negative e rispondere adeguatamente alle domande che gli sviluppi della biologia, della medicina e delle tecnologie bioingegneristiche pongono, la Convenzione raccomandava che i Paesi firmatari avviassero dei dibattiti pubblici appropriati alla luce delle implicazioni mediche, sociali, economiche, etiche e giuridiche pertinenti e che fossero oggetto di consultazioni pubbliche.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Viene chiesto un dibattito pubblico sostenuto da un'informazione trasparente e di qualità per aiutare tutti, ma soprattutto i pazienti e le famiglie a superare il loro isolamento culturale e psicologico e contribuire così alla costruzione di una vera cittadinanza scientifica</span><span style="-webkit-text-size-adjust: auto; background-color: white; font-family: Helvetica, Arial, sans-serif; font-size: 12px; line-height: 16px;">.</span></div>
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-31106391231555916122014-03-29T05:34:00.001-07:002014-07-14T08:49:09.335-07:00Parigi, Venezia, 12 febbraio 2014
Lettera aperta al Ministro italiano della Salute Beatrice Lorenzin sulla necessità di un dibattito pubblico informato sulle terapie con cellule staminali e la corretta, sicura ed etica attuazione di trattamenti medici efficaci
La situazione attuale
Oggi, tra 6.000 e 8.000 malattie rare colpiscono circa 2,5 milioni di persone in Italia, la maggioranza delle quali non ha alcuna possibilità di cura. Per moltissimi cittadini affetti da malattie rare e per le loro famiglie la vita quotidiana è una battaglia, la prospettiva di una cura o di una terapia appropriata è ciò che sognano e per cui lottano. Per una cura possibile i pazienti, le famiglie e le loro organizzazioni interagiscono e lavorano attivamente per essere "soggetti di ricerca ", non solo attraverso il loro coinvolgimento diretto e consapevole nelle sperimentazioni cliniche, la raccolta dei dati e la messa a disposizione di campioni biologici, ma anche aiutando ad indirizzare, valutare, monitorare la ricerca attraverso un dialogo costante con tutti gli attori coinvolti, partecipando a comitati etici e commissioni regolatorie, attraverso la raccolta di fondi, mettendo a disposizione le proprie competenze, conoscenze, esperienze ed energie ovunque siano necessarie.
I cittadini italiani si sono posti molte domande di fronte alle promesse offerte dal metodo Stamina, in particolare, i pazienti italiani e le famiglie colpite dalle malattie rare alle quali la Fondazione Stamina sembrava offrire speranze. Tuttavia a questi pazienti e cittadini non sono stati forniti gli strumenti per fare una scelta informata.
Non solo le necessarie informazioni sul metodo Stamina non sono state divulgate, ma regna tuttora l'incertezza sulle conclusioni del Comitato Scientifico chiamato nel 2013 a valutare tale metodo. Ulteriore confusione è stata generata a seguito della sentenza del TAR del Lazio n. 08730/2013 REG.RIC. che ha messo in discussione la legittimità del suddetto Comitato Scientifico. Infine, il dibattito pubblico è stato dominato da dichiarazioni scandalistiche da parte dei media, fatto che ha portato a una situazione caotica.
Come rappresentanti dei pazienti guardiamo con sgomento a questi risultati: è stata persa una grande opportunità di informazione e di comunicazione pubblica e si è creato un grave divario tra i cittadini e le istituzioni. I pazienti e le famiglie, che spesso sono soli nella loro lotta quotidiana contro la malattia e in assoluta necessità di cure, si sono trovati ancora più isolati di fronte a una scelta cruciale, per sé o per i propri cari. Si deve porre rimedio a questa situazione, assicurandosi altresì che essa non si ripeta mai più.
Beatrice Lorenzin Ministro della Salute Via Lungotevere Ripa, 1 00153 ROMAAnonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-78126193717993821742014-03-29T05:29:00.001-07:002014-07-14T08:49:09.341-07:00Oltre il metodo Stamina: lettera aperta al Ministro Lorenzin di EURORDIS e UNlAMO FIMR onlus
Ultimo aggiornamento Venerdì 07 Marzo 2014 17:26
Giovedì 06 Marzo 2014 16:47
EURORDIS, l'Organizzazione Europea per le Malattie Rare, e UNIAMO Federazione Italiana Malattie Rare, inviano una lettera aperta al Ministro italiano della Salute Beatrice Lorenzin
sulla necessità di un dibattito pubblico informato sulle terapie con cellule staminali e la corretta, sicura ed etica attuazione di trattamenti medici efficaci in occasione della nomina del nuovo Comitato scientifico per la valutazione del cosiddetto Metodo Stamina. In particolare si chiede al Ministro italiano della Salute di rimediare all'estesa confusione generatasi in questi mesi attraverso:
• la divulgazione delle informazioni rilevanti, ad oggi non accessibili al pubblico;
• l'esposizione dei concetti fondamentali in gioco, indispensabile per fornire un'informazione accurata sulla vicenda Stamina.
Fondamentale l'appello al Ministro della Salute affinché divulghi prima dell'insediamento della nuova commissione i risultati dei lavori del Comitato Scientifico del 2013; si invita inoltre il Ministro a confermare che sarà valutato lo stesso protocollo. Ciò eviterebbe la circolazione attraverso i media di ulteriori dichiarazioni infondate, a favore o contro il metodo Stamina, e renderebbe le informazioni disponibili a chiunque, al fine di giudicare autonomamente sulla base di dati oggettivi. Di conseguenza il nuovo Comitato dovrebbe operare senza la restrizione di accordi di riservatezza in modo tale da poter offrire tutti i dati, i verbali e le decisioni finali alla valutazione e alla comprensione del pubblico, dei pazienti interessati e delle loro famiglie.
È importantissimo che il Governo italiano svolga la sua missione istituzionale e, nel perseguimento dell'interesse pubblico, contribuisca ad attivare processi di comunicazione trasparente e di informazione pubblica su una possibilità di cura a così alto impatto individuale e sociale.
La lettera integrale inviata al Ministro è scaricabile in allegato, mentre clicca qui per la lettera in inglese sul sito di EURORDIS
Allegati:
Lettera aperta UNIAMO - EURORDIS 357 Kb
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-59388673567809610032014-03-29T05:24:00.003-07:002014-03-29T05:24:31.100-07:00<div class="article-rel-wrapper">
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);">Le Malattie Rare sono una Priorità di Sanità pubblica per il Governo italiano?</span></span></h2>
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<span class="modifydate" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Ultimo aggiornamento Venerdì 28 Marzo 2014 21:05</span></span><span class="createdate" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Venerdì 28 Marzo 2014 21:02</span></span></div>
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<strong style="background-color: rgba(255, 255, 255, 0);"><strong>Questo è quanto si chiede UNIAMO FIMR onlus in una pagina su Il Sole 24Ore.</strong></strong></div>
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<span style="background-color: rgba(255, 255, 255, 0);"><strong>Domenica 30 marzo 2014</strong> UNIAMO Federazione Italiana Malattie Rare onlus pubblicherà su Il Sole 24Ore <strong>una pagina intera</strong> <strong>per ricordare</strong> al Ministro della Salute Beatrice Lorenzin <strong>non solo l'impegno preso dall'Italia in sede europea di adottare il Piano Nazionale Malattie Rare entro il 2013, ma che questo piano deve essere aggiornato nei suoi contenuti</strong> prima di essere sottoposto al vaglio della Conferenza Stato-Regioni per essere realmente uno strumento chiave per una nuova e più efficace governance delle malattie rare</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Nel testo la Federazione sottopone all'attenzione del Ministro <strong>i 10 punti chiave per la Governance delle malattie rare</strong>, scaturiti dalla Conferenza Nazionale Europlan II, iniziativa che ha visto la partecipazione di oltre 160 delegati di diversi Enti portatori di interesse nel sistema delle malattie rare. I delegati, con una modalità partecipativa innovativa, hanno prodotto un documento che ha analizzato criticità e best practices intorno a 6 temi coerenti con le aree di obiettivo della bozza del Piano presentata dall'allora Ministero della Salute il 18 dicembre 2012.</span></div>
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<strong>Il documento elaborato offre un quadro esaustivo degli interventi necessari per offrire un'assistenza adeguata e omogenea ai malati rari sul territorio nazionale</strong>.</div>
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<strong style="background-color: rgba(255, 255, 255, 0);">E' necessario adattare un importante strumento, quale il Piano Nazionale Malattie Rare, alle reali necessità dei pazienti, delle famiglie e degli stessi operatori sanitari e socio-sanitari.</strong></div>
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<span style="background-color: rgba(255, 255, 255, 0);">I 10 punti che UNIAMO, in qualità di portavoce dei diversi portatori di interesse coinvolti in questo delicato tema, porta all'attenzione del Ministro e dell'opinione pubblica, sono l'espressione della comunità dei malati rari e devono essere fonte di indirizzo nell'elaborazione finale dello stesso PNMR e delle politiche socio-sanitarie territoriali.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">La Federazione segnala, inoltre, che <strong>l'Italia non ha ancora nominato il rappresentante ufficiale e il suo sostituito in sede di EUCERD</strong>, il gruppo tecnico di esperti per le malattie rare a supporto della Commissione Europea, altro fondamentale strumento per la Governance europea del tema malattie rare</span><span style="-webkit-text-size-adjust: auto; background-color: white; font-family: Helvetica, Arial, sans-serif; font-size: 12px; line-height: 16px;">.</span></div>
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-82469653876296705322014-03-19T03:42:00.002-07:002014-03-19T03:42:22.844-07:00Conoscenza delle Febbri periodiche, diagnosi e cura<img src="webkit-fake-url://B634FBE3-D5CB-4448-861B-77016D3CC468/imagejpeg" />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-35572902899303370722014-02-07T14:46:00.002-08:002014-02-07T14:47:30.369-08:00<div align="justify">
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La Conferenza Europea 2014 sulle Malattie Rare e i Farmaci Orfani presenta un programma molto ricco</div>
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<span style="background-color: rgba(255, 255, 255, 0);">È il turno di Berlino di ospitare la 7a edizione della Conferenza biennale Europea sulle Malattie Rare e i Farmaci Orfani (8-10 maggio 2014) e per la quale è stato annunciato questo mese un programma molto ricco. Questa conferenza, organizzata dall’Organizzazione Europea per le Malattie Rare (EURORDIS) e da DIA Europe, è l’unico evento dedicato all’informazione sullo stato dell’arte delle attività nel campo delle malattie rare, in settori che variano dalla ricerca alle cure mediche, all’assistenza sociale e all’accesso ai farmaci orfani. La conferenza rappresenta un luogo di incontro unico per la comunità delle malattie rare, mettendo in contatto rappresentanti di diverse malattie e gruppi di portatori di interesse in Europa ed anche oltre e fornendo la perfetta opportunità di condividere conoscenze ed esperienze.<br /><br />L’ultima edizione di questa conferenza di grande successo, che conta la partecipazione di quasi 700 persone ogni due anni, ha come obiettivo di dimostrare l’importanza delle azioni a livello europeo nel campo delle malattie rare e di fare il punto sull’evoluzione di questo tema. Gli organizzatori mirano anche a sostenere una dinamica a livello europeo nel campo delle malattie rare, considerando le prospettive future di una vasta gamma di argomenti che costituiscono i pezzi del puzzle delle malattie rare.<br /><br />Il programma della conferenza, ora disponibile online <a class="Url" href="http://www.rare-diseases.eu/programme" style="font-weight: bold;" target="_blank">per saperne di più</a>), prevede sessioni parallele sui seguenti temi principali: migliorare i servizi sanitari; ampliamento delle conoscenze e divulgazione; ricerca dalle scoperte ai pazienti; stato dell'arte e progressi dei farmaci orfani; nuovi concetti e politiche future per il trattamento delle malattie rare; oltre l’assistenza medica. Queste sessioni forniranno l'opportunità di condividere sia esperienze reali che buone pratiche, mirando a stimolare la consapevolezza, il dibattito e il networking in un approccio specifico per garantire che tutti possano beneficiare delle lezioni apprese nel corso degli ultimi due anni.<br /><br />La conferenza si terrà in lingua inglese e verrà offerto un servizio di interpretariato per le sessioni di apertura e plenarie (in francese, spagnolo, tedesco, polacco e russo). Il giorno che precede la conferenza principale sarà ancora una volta dedicato alle sessioni di capacity building per i malati e i loro rappresentanti, oltre che al tutorial dedicato ai rappresentanti dell'industria e ai partecipanti provenienti dal mondo accademico. Sono state inserite nel programma anche numerose opportunità di networking per permettere ai partecipanti di crearsi nuovi contatti da aggiungere alle proprie rubriche. Le sessioni dedicate ai poster forniranno invece una grande opportunità di scambio di informazioni e di know-how sui temi principali.<br /><br />Gli organizzatori incoraggiano tutti gli attori della comunità delle malattie rare, i rappresentanti dei pazienti, i politici, i ricercatori, i professionsti del settore e le autorità di regolamentazione a partecipare alla conferenza e di decretarne, ancora una volta, il successo. Il programma della conferenza è ora disponibile online (<a class="Url" href="http://www.rare-diseases.eu/programme" style="font-weight: bold;" target="_blank">Per saperne di più</a>) ed è aperta la registrazione online (<a class="Url" href="http://www.rare-diseases.eu/registration/" style="font-weight: bold;" target="_blank">Registrati qui</a>).</span></div>
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-21646953865003454672014-01-13T13:47:00.000-08:002014-01-13T13:47:01.248-08:00GIORNATAMONDIALE DELLE MALATTIE RARE<br />
28/02/2014<br />
ECCO ALCUNI LINK MOLTO INTERESSANTI<br />
<a href="http://www.eurordis.org/it/news/partecipa-alla-giornata-delle-malattie-rare-2014-e-unisciti-un-assistenza-migliore">http://www.eurordis.org/it/news/partecipa-alla-giornata-delle-malattie-rare-2014-e-unisciti-un-assistenza-migliore</a><br />
<a href="http://www.uniamo.org/it/news/news-uniamo/597-giornata-delle-malattie-rare-2014-uniti-per-una-assistenza-migliore.html">http://www.uniamo.org/it/news/news-uniamo/597-giornata-delle-malattie-rare-2014-uniti-per-una-assistenza-migliore.html</a><br />
<a href="http://www.rarediseaseday.org/">http://www.rarediseaseday.org/</a><br />
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<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-80736504187776040532013-11-14T00:52:00.004-08:002013-11-14T00:52:59.244-08:00<br />
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<span style="font-size: 12pt; font-weight: 700;">Successful Treatment of Chronic Recurrent Multifocal Osteomyelitis With
Tumor Necrosis Factor- </span><span style="font-family: 'Symbol'; font-size: 12.000000pt;">α </span><span style="font-size: 12pt; font-weight: 700;">Blockage<br />
</span><span style="font-size: 12pt;">Andrea Deutschmann, Christoph J. Mache, Koppany Bodo, Doris Zebedin and
</span><br />
<span style="font-size: 12pt;">Ekkehard Ring
</span><span style="font-size: 12pt; font-style: italic;">Pediatrics </span><span style="font-size: 12pt;">2005;116;1231
DOI: 10.1542/peds.2004-2206 </span><br />
<span style="font-size: 12pt;"><br /></span>
<span style="font-size: 12pt;"><a href="http://pediatrics.aappublications.org/content/116/5/1231.full.pdf">http://pediatrics.aappublications.org/content/116/5/1231.full.pdf</a></span><br />
<span style="font-size: 12pt;"><br /></span>
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Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com1tag:blogger.com,1999:blog-6684601906212672304.post-62070528557180001142013-11-09T09:05:00.004-08:002013-11-09T09:05:56.324-08:00<div class="separator" style="clear: both; text-align: center;">
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<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-91706870900943548502013-11-09T09:05:00.001-08:002013-11-09T09:05:08.610-08:00DISEASOME ............ECCO IL ILNK<br />
<a href="http://diseasome.eu/map.html">http://diseasome.eu/map.html</a><br />
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<br />Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-3270175747587702362013-11-09T08:59:00.000-08:002013-11-09T09:00:18.191-08:00<h1 id="article-title-1" itemprop="headline" style="background-color: white; border: 0px; color: #202020; font-family: 'Open Sans', sans-serif !important; font-size: 24px; font-weight: normal; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; vertical-align: baseline;">
The human disease network</h1>
<div class="contributors" style="background-color: white; border: 0px; color: #333333; font-family: Arial, sans-serif; font-size: 14px; line-height: 18px; margin: 0px; outline-style: none; padding: 0px; vertical-align: baseline;">
<ol class="contributor-list" id="contrib-group-1" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; list-style: none; margin: 15px 0px 0px; outline-style: none; padding: 0px; vertical-align: baseline;">
<li id="contrib-1" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Kwang-Il+Goh&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Kwang-Il Goh</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-1" id="xref-aff-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">*</a> <span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-5" id="xref-aff-5-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">§</span> </a>, </li>
<li id="contrib-2" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Michael+E.+Cusick&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Michael E. Cusick</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-3" id="xref-aff-3-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">¶</span> </a>, </li>
<li id="contrib-3" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=David+Valle&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">David Valle</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-6" id="xref-aff-6-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‖</span> </a>, </li>
<li id="contrib-4" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Barton+Childs&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Barton Childs</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-6" id="xref-aff-6-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‖</span> </a>, </li>
<li id="contrib-5" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Marc+Vidal&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Marc Vidal</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-3" id="xref-aff-3-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">¶</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-corresp" href="http://www.pnas.org/content/104/21/8685.full#corresp-1" id="xref-corresp-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">**</a>, and </li>
<li id="contrib-6" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Albert-L%C3%A1szl%C3%B3+Barab%C3%A1si&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Albert-László Barabási</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-1" id="xref-aff-1-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">*</a> <span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-corresp" href="http://www.pnas.org/content/104/21/8685.full#corresp-1" id="xref-corresp-1-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">**</a></li>
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Edited by H. Eugene Stanley, Boston University, Boston, MA, and approved April 3, 2007 (received for review February 14, 2007)</div>
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Abstract</h2>
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A network of disorders and disease genes linked by known disorder–gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.</div>
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<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=biological+networks&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">biological networks</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=complex+networks&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">complex networks</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=human+genetics&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">human genetics</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=systems+biology&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">systems biology</a></span></li>
<li class="kwd" style="border: none; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=diseasome&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">diseasome</a></span></li>
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Decades-long efforts to map human disease loci, at first genetically and later physically (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-1" id="xref-ref-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">1</a>), followed by recent positional cloning of many disease genes (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-2" id="xref-ref-2-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">2</a>) and genome-wide association studies (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-3" id="xref-ref-3-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">3</a>), have generated an impressive list of disorder–gene association pairs (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-4" id="xref-ref-4-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">4</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-5" id="xref-ref-5-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">5</a>). In addition, recent efforts to map the protein–protein interactions in humans (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-7" id="xref-ref-7-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">7</a>), together with efforts to curate an extensive map of human metabolism (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-8" id="xref-ref-8-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">8</a>) and regulatory networks offer increasingly detailed maps of the relationships between different disease genes. Most of the successful studies building on these new approaches have focused, however, on a single disease, using network-based tools to gain a better understanding of the relationship between the genes implicated in a selected disorder (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-9" id="xref-ref-9-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">9</a>).</div>
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Here we take a conceptually different approach, exploring whether human genetic disorders and the corresponding disease genes might be related to each other at a higher level of cellular and organismal organization. Support for the validity of this approach is provided by examples of genetic disorders that arise from mutations in more than a single gene (locus heterogeneity). For example, Zellweger syndrome is caused by mutations in any of at least 11 genes, all associated with peroxisome biogenesis (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-10" id="xref-ref-10-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">10</a>). Similarly, there are many examples of different mutations in the same gene (allelic heterogeneity) giving rise to phenotypes currently classified as different disorders. For example, mutations in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">TP53</em> have been linked to 11 clinically distinguishable cancer-related disorders (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-11" id="xref-ref-11-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">11</a>). Given the highly interlinked internal organization of the cell (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-12" id="xref-ref-12-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">12</a>–<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-17" id="xref-ref-17-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">17</a>), it should be possible to improve the single gene–single disorder approach by developing a conceptual framework to link systematically all genetic disorders (the human “disease phenome”) with the complete list of disease genes (the “disease genome”), resulting in a global view of the “diseasome,” the combined set of all known disorder/disease gene associations.</div>
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Results</h2>
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Construction of the Diseasome.</h3>
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We constructed a bipartite graph consisting of two disjoint sets of nodes. One set corresponds to all known genetic disorders, whereas the other set corresponds to all known disease genes in the human genome (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F1" id="xref-fig-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 1</a>). A disorder and a gene are then connected by a link if mutations in that gene are implicated in that disorder. The list of disorders, disease genes, and associations between them was obtained from the Online Mendelian Inheritance in Man (OMIM; ref. <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-18" id="xref-ref-18-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">18</a>), a compendium of human disease genes and phenotypes. As of December 2005, this list contained 1,284 disorders and 1,777 disease genes. OMIM initially focused on monogenic disorders but in recent years has expanded to include complex traits and the associated genetic mutations that confer susceptibility to these common disorders (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-18" id="xref-ref-18-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">18</a>). Although this history introduces some biases, and the disease gene record is far from complete, OMIM represents the most complete and up-to-date repository of all known disease genes and the disorders they confer. We manually classified each disorder into one of 22 disorder classes based on the physiological system affected [see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">supporting information (SI) <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">Text</em>, SI Fig. 5, and SI Table 1</a> for details].</div>
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Construction of the diseasome bipartite network. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">Center</em>) A small subset of OMIM-based disorder–disease gene associations (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-18" id="xref-ref-18-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">18</a>), where circles and rectangles correspond to disorders and disease genes, respectively. A link is placed between a disorder and a disease gene if mutations in that gene lead to the specific disorder. The size of a circle is proportional to the number of genes participating in the corresponding disorder, and the color corresponds to the disorder class to which the disease belongs. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">Left</em>) The HDN projection of the diseasome bipartite graph, in which two disorders are connected if there is a gene that is implicated in both. The width of a link is proportional to the number of genes that are implicated in both diseases. For example, three genes are implicated in both breast cancer and prostate cancer, resulting in a link of weight three between them. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">Right</em>) The DGN projection where two genes are connected if they are involved in the same disorder. The width of a link is proportional to the number of diseases with which the two genes are commonly associated. A full diseasome bipartite map is provided as <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 13</a>.</div>
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Starting from the diseasome bipartite graph we generated two biologically relevant network projections (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F1" id="xref-fig-1-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 1</a>). In the “human disease network” (HDN) nodes represent disorders, and two disorders are connected to each other if they share at least one gene in which mutations are associated with both disorders (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F1" id="xref-fig-1-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Figs. 1</a> and<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). In the “disease gene network” (DGN) nodes represent disease genes, and two genes are connected if they are associated with the same disorder (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F1" id="xref-fig-1-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Figs. 1</a> and <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>). Next, we discuss the potential of these networks to help us understand and represent in a single framework all known disease gene and phenotype associations.</div>
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The HDN and the DGN. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>) In the HDN, each node corresponds to a distinct disorder, colored based on the disorder class to which it belongs, the name of the 22 disorder classes being shown on the right. A link between disorders in the same disorder class is colored with the corresponding dimmer color and links connecting different disorder classes are gray. The size of each node is proportional to the number of genes participating in the corresponding disorder (see key), and the link thickness is proportional to the number of genes shared by the disorders it connects. We indicate the name of disorders with >10 associated genes, as well as those mentioned in the text. For a complete set of names, see<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 13</a>. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>) In the DGN, each node is a gene, with two genes being connected if they are implicated in the same disorder. The size of each node is proportional to the number of disorders in which the gene is implicated (see key). Nodes are light gray if the corresponding genes are associated with more than one disorder class. Genes associated with more than five disorders, and those mentioned in the text, are indicated with the gene symbol. Only nodes with at least one link are shown.</div>
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Properties of the HDN.</h3>
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If each human disorder tends to have a distinct and unique genetic origin, then the HDN would be disconnected into many single nodes corresponding to specific disorders or grouped into small clusters of a few closely related disorders. In contrast, the obtained HDN displays many connections between both individual disorders and disorder classes (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). Of 1,284 disorders, 867 have at least one link to other disorders, and 516 disorders form a giant component, suggesting that the genetic origins of most diseases, to some extent, are shared with other diseases. The number of genes associated with a disorder, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">s</em>, has a broad distribution (see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 6<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em> </a>), indicating that most disorders relate to a few disease genes, whereas a handful of phenotypes, such as deafness (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">s</em> = 41), leukemia (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">s</em> = 37), and colon cancer (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">s</em> = 34), relate to dozens of genes (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). The degree (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">k</em>) distribution of HDN (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 6<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em> </a>) indicates that most disorders are linked to only a few other disorders, whereas a few phenotypes such as colon cancer (linked to <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">k</em> = 50 other disorders) or breast cancer (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">k</em> = 30) represent hubs that are connected to a large number of distinct disorders. The prominence of cancer among the most connected disorders arises in part from the many clinically distinct cancer subtypes tightly connected with each other through common tumor repressor genes such as <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">TP53</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">PTEN</em>.</div>
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Although the HDN layout was generated independently of any knowledge on disorder classes, the resulting network is naturally and visibly clustered according to major disorder classes. Yet, there are visible differences between different classes of disorders. Whereas the large cancer cluster is tightly interconnected due to the many genes associated with multiple types of cancer (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">TP53</em>, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">KRAS</em>, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">ERBB2</em>, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">NF1</em>, etc.) and includes several diseases with strong predisposition to cancer, such as Fanconi anemia and ataxia telangiectasia, metabolic disorders do not appear to form a single distinct cluster but are underrepresented in the giant component and overrepresented in the small connected components (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-5" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). To quantify this difference, we measured the locus heterogeneity of each disorder class and the fraction of disorders that are connected to each other in the HDN (see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">SI Text</em> </a>). We find that cancer and neurological disorders show high locus heterogeneity and also represent the most connected disease classes, in contrast with metabolic, skeletal, and multiple disorders that have low genetic heterogeneity and are the least connected (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 7</a>).</div>
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Properties of the DGN.</h3>
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In the DGN, two disease genes are connected if they are associated with the same disorder, providing a complementary, gene-centered view of the diseasome. Given that the links signify related phenotypic association between two genes, they represent a measure of their phenotypic relatedness, which could be used in future studies, in conjunction with protein–protein interactions (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-7" id="xref-ref-7-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">7</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-19" id="xref-ref-19-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">19</a>), transcription factor-promoter interactions (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-20" id="xref-ref-20-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">20</a>), and metabolic reactions (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-8" id="xref-ref-8-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">8</a>), to discover novel genetic interactions. In the DGN, 1,377 of 1,777 disease genes are connected to other disease genes, and 903 genes belong to a giant component (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-6" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>). Whereas the number of genes involved in multiple diseases decreases rapidly (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 6<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em> </a>; light gray nodes in <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-7" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>), several disease genes (e.g., <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">TP53</em>, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">PAX6</em>) are involved in as many as 10 disorders, representing major hubs in the network.</div>
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Functional Clustering of HDN and DGN.</h3>
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To probe how the topology of the HDN and GDN deviates from random, we randomly shuffled the associations between disorders and genes, while keeping the number of links per each disorder and disease gene in the bipartite network unchanged. Interestingly, the average size of the giant component of 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">4</span> randomized disease networks is 643 ± 16, significantly larger than 516 (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−4</span>; for details of statistical analyses of the results reported hereafter, see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">SI Text</em> </a>), the actual size of the HDN (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 6<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em> </a>). Similarly, the average size of the giant component from randomized gene networks is 1,087 ± 20 genes, significantly larger than 903 (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−4</span>), the actual size of the DGN (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 6<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">e</em></a>). These differences suggest important pathophysiological clustering of disorders and disease genes. Indeed, in the actual networks disorders (genes) are more likely linked to disorders (genes) of the same disorder class. For example, in the HDN there are 812 links between disorders of the same class, an 8-fold enrichment with respect to 107 ± 10 links obtained between the same set of nodes in the randomized networks. This local functional clustering accounts for the small size of the giant components observed in the actual networks.</div>
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Disease-Associated Genes Identify Distinct Functional Modules.</h3>
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For several disorders known to arise from mutations in any one of a few distinct genes, the corresponding protein products have been shown to participate in the same cellular pathway, molecular complex, or functional module (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-21" id="xref-ref-21-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">21</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-22" id="xref-ref-22-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">22</a>). For example, Fanconi anemia arises from mutations in a set of genes encoding proteins involved in DNA repair, many of them forming a single heteromeric complex (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-23" id="xref-ref-23-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">23</a>). Yet, the extent to which most disorders and disorder classes correspond to distinct functional modules in the cellular network has remained largely unclear. If genes linked by disorder associations encode proteins that interact in functionally distinguishable modules, then the proteins within such disease modules should more likely interact with one another than with other proteins. To test this hypothesis, we overlaid the DGN on a network of physical protein–protein interactions derived from high-quality systematic interactome mapping (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-7" id="xref-ref-7-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">7</a>) and literature curation (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>). We found that 290 interactions overlap between the two networks, a 10-fold increase relative to random expectation (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F3" id="xref-fig-3-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 3</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>).</div>
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Characterizing the disease modules. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>) Number of observed physical interactions between the products of genes within the same disorder (red arrow) and the distribution of the expected number of interactions for the random control (blue) (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>). (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>) Distribution of the tissue-homogeneity of a disorder (red). Random control (blue) with the same number of genes chosen randomly is shown for comparison. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em>) The distribution of PCC ρ<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"> <span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">ij</span></em>values of the expression profiles of each disease gene pair that belongs to the same disorder (red) and the control (blue), representing the PCC distribution between all gene pairs (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>). (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em>) Distribution of the average PCC between expression profiles of all genes associated with the same disorder (red) is also shifted toward higher values than the random control (blue) with the same number of genes chosen randomly (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>).</div>
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Genes associated with the same disorder share common cellular and functional characteristics, as annotated in the Gene Ontology (GO) (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-24" id="xref-ref-24-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">24</a>). If the HDN shows modular organization, then a group of genes associated with the same common disorder should share similar cellular and functional characteristics, as annotated in GO. To investigate the validity of this hypothesis, we measured the GO homogeneity of each disorder (see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">SI Text</em> </a>) separately for each branch of GO, biological process, molecular function, and cellular component, finding significant elevation of GO homogeneity with respect to random controls in all three branches (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 8</a>).</div>
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Disease genes encoding proteins that interact within common functional modules should tend to be expressed in the same tissue. To measure this, we introduced the tissue-homogeneity coefficient of a disorder, defined as the maximum fraction of genes among those belonging to a common disorder that are expressed in a specific tissue in a microarray data set obtained for 10,594 genes across 36 healthy tissues (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-25" id="xref-ref-25-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">25</a>). We found that 68% of disorders exhibited almost perfect tissue-homogeneity (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F3" id="xref-fig-3-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 3</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>), compared with 51% expected by chance (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−5</span>).</div>
<div id="p-18" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">
Finally, disease genes that participate in a common functional module should also show high expression profiling correlation (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-26" id="xref-ref-26-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">26</a>). The distribution of Pearson correlation coefficients (PCCs) for the coexpression profiles of pairs of genes associated with the same disorder was shifted toward higher values compared with that of a random control (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F3" id="xref-fig-3-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 3</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em>; <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>, χ<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">2</span> test). Similarly, the average PCC over all pairs of genes within a given disorder shows a significant shift from the random reference (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F3" id="xref-fig-3-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 3</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em>), with a small but clearly distinguishable peak in the distribution around PCC ≈ 0.75. This peak corresponds to ≈33 disorders with average PCC > 0.6 for which all genes are highly coexpressed in most tissues, including Heinz body anemia (PCC = 0.935), Bethlem myopathy (PCC = 0.835), and spherocytosis (PCC = 0.656).</div>
<div id="p-19" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">
In summary, genes that contribute to a common disorder (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">i</em>) show an increased tendency for their products to interact with each other through protein–protein interactions, (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">ii</em>) have a tendency to be expressed together in specific tissues, (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">iii</em>) tend to display high coexpression levels, (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">iv</em>) exhibit synchronized expression as a group, and (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">v</em>) tend to share GO terms. Together, these findings support the hypothesis of a global functional relatedness for disease genes and their products and offer a network-based model for the diseasome. Cellular networks are modular, consisting of groups of highly interconnected proteins responsible for specific cellular functions (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-21" id="xref-ref-21-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">21</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-22" id="xref-ref-22-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">22</a>). A disorder then represents the perturbation or breakdown of a specific functional module caused by variation in one or more of the components producing recognizable developmental and/or physiological abnormalities.</div>
<div id="p-20" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">
This model offers a network-based explanation for the emergence of complex or polygenic disorders: a phenotype often correlates with the inability of a particular functional module to carry out its basic functions. For extended modules, many different combinations of perturbed genes could incapacitate the module, as a result of which mutations in different genes will appear to lead to the same phenotype. This correlation between disease and functional modules can also inform our understanding of cellular networks by helping us to identify which genes are involved in the same cellular function or network module (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-21" id="xref-ref-21-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">21</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-22" id="xref-ref-22-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">22</a>).</div>
<h3 style="border: 0px; color: #202020; display: inline; font-family: 'Open Sans', sans-serif !important; font-size: 18px; font-style: inherit; font-weight: normal; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Centrality and Peripherality.</h3>
<br />
<div class="h-lead h3-h-lead" id="p-21" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">
An early indication of the connection between the structure of a cellular network and its functional properties was the finding that in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">Saccharomyces cerevisiae</em> highly connected proteins or “hubs” are more likely encoded by essential genes (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-15" id="xref-ref-15-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">15</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-16" id="xref-ref-16-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">16</a>). This prompted a number of recent studies (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-27" id="xref-ref-27-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">27</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-28" id="xref-ref-28-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">28</a>) to formulate the hypothesis that human disease genes should also have a tendency to encode hubs. Yet, previous measurements found only a weak correlation between disease genes and hubs (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-29" id="xref-ref-29-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">29</a>), resulting in an important mystery: what is the role, if any, of the cellular network in human diseases? Are disease genes more likely to encode hubs in the cellular network?</div>
<div id="p-22" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">
Our initial analysis appears to support the hypothesis that disease genes, given their impact on the organism, display a tendency to encode hubs in the interactome (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-27" id="xref-ref-27-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">27</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-28" id="xref-ref-28-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">28</a>), finding that disease related proteins have a 32% larger number of interactions (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-5" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-7" id="xref-ref-7-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">7</a>) with other proteins (average degree) than the nondisease proteins (see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig 9</a>) and that high-degree proteins are more likely to be encoded by genes associated with diseases than proteins with few interactions (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 1.6 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−17</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). Next, we show, however, that despite this apparent correlation, the relationship between diseases and hubs hides deep differences between various disease genes.</div>
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<div class="first-child" id="p-23" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.5; margin-bottom: 15px; margin-top: 15px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Functional characteristics of disease and essential genes. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>) The fraction of disease genes among those whose protein products that interact with <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">k</em> other proteins. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>) Venn diagram showing the relationship between the human genes studied in this work. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em>) The fraction of genes with lethal mouse phenotypes (essential genes) among those with mouse phenotypes that interact with <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">k</em>other proteins. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em>) The same as in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>, but only for nonessential disease genes, i.e., excluding 398 proteins with lethal mouse phenotypes. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">e</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">f</em>) The fraction of essential genes (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">e</em>) and nonessential disease genes (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">f</em>) among those whose average PCC with other genes is 〈ρ〉. (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">g</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">h</em>) The fraction of essential genes (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">g</em>) and nonessential disease genes (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">h</em>) among those whose transcript is expressed in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">n<span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">T</span> </em>tissues. Gray horizontal lines in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em> and <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c–h</em> indicate the global average. Error bars represent standard errors. Note that for some data points the error bars are smaller than the symbol size, and thus are not visible. In <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>, <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em>, and <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em> gray symbols are the linearly binned data points, whereas color corresponds to the statistically more uniform log-binned data. For details of the significance analysis, see <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">SI Text</em> </a>.</div>
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When exploring whether disease genes encode hubs, we, and authors of other earlier studies (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-27" id="xref-ref-27-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">27</a>–<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-29" id="xref-ref-29-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">29</a>), ignored the fact that some human genes are essential in early development and functional changes in these contribute to the high rate of first-trimester spontaneous abortions, which might be as much as 20% of recognized pregnancies. One strategy to explore the impact of this <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">in utero</em> essential segment of human disease is to consider human orthologs of mouse genes that result in embryonic or postnatal lethality when disrupted by homologous recombination (Mouse Genome Informatics; <a href="http://www.informatics.jax.org/" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">www.informatics.jax.org</a>). All together, we find 1,267 such mouse lethal orthologs of human genes, of which 398 are associated with human diseases, representing 22% of all known human disease genes. This allows us to distinguish between two classes of human genes: 1,267 “essential genes” and 1,379 “nonessential disease genes,” the latter obtained by removing from the full list of 1,777 OMIM disease genes the 398 that are also essential (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a><em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">b</em>). Next, we show that these two classes of genes play quite different roles in the human interactome.</div>
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First, we find that essential proteins show a tendency to be associated with hubs (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 1.3 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−17</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">c</em>), displaying a much stronger trend than the one observed for all disease proteins (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>). This raises an important question: Could the observed correlation between disease genes and hubs (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-5" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>) be the sole consequence of the fact that a small fraction (22%) of disease genes is also essential? To address this question we measured the degree dependence of the nonessential disease proteins (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-6" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">d</em>). Surprisingly, the correlation between hubs and disease proteins entirely disappears. Thus, the vast majority of disease genes (78%), those that are nonessential, do not show a tendency to encode hubs, indicating that the observed weak correlations between hubs and disease genes (<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-7" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">a</em>) was entirely due to the few essential genes within the disease gene class.</div>
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To carry on its basic functions, the cell needs to maintain the coordinated activity of important functional modules, driving in a relatively synchronized manner the expression patterns of the most important genes. Therefore, one expects that the expression pattern of both essential and disease genes will be synchronized with a significant number of other genes. To test this, we determined the average gene coexpression coefficient 〈ρ〉<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"> <span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">i</span> </em>= Σ<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"> <span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">j</span> </em>PCC<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"> <span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">ij</span> </em>between an essential (or nonessential disease) gene <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">i</em> and all other genes in the cell, calculating the PCC<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"> <span style="border: 0px; bottom: -0.25em; font-family: inherit; font-size: 11px; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; vertical-align: baseline;">ij</span> </em>values from healthy human tissue microarray measurements (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-25" id="xref-ref-25-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">25</a>). Confirming our expectation, for essential genes we find that genes that display high average coexpression 〈ρ〉 with all other genes are more likely to be essential than those that show small or negative 〈ρ〉 (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 1.7 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−4</span>;<a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-8" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">e</em>). Surprisingly, however, nonessential disease genes show the opposite effect, being associated with genes whose expression pattern is anticorrelated or not-correlated with other genes, and underrepresented among the genes that are highly synchronized (〈ρ〉 > 0.2) (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 2.6 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−8</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-9" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">f</em>). Thus, the expression pattern of nonessential disease genes appears to be decoupled from the overall expression pattern of all other genes, whereas essential genes have a tendency to be coupled to the rest of the cell.</div>
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Finally, we asked whether housekeeping genes, expressed in all tissues, have a tendency to encode disease genes. We find that the more tissues in which a gene is expressed, the higher the likelihood that it will be essential (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 2.8 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−16</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-10" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">g</em>). The opposite is true for nonessential disease genes: they have a tendency to be expressed in a few tissues (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 1.4 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>; <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-11" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">h</em>). Similarly, we found that only 9.9% of housekeeping genes correspond to disease genes, compared with 13.5% of nonhousekeeping genes, a significant 36% difference (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> = 3.6 × 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−6</span>). In contrast, 59.8% of housekeeping genes annotated with mouse phenotype were essential, compared with 40.5% for nonhousekeeping genes (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">P</em> < 10<span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">−4</span>).</div>
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These results support the somewhat unexpected conclusion that nonessential disease genes are not associated with hubs (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-27" id="xref-ref-27-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">27</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-28" id="xref-ref-28-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">28</a>), show smaller correlation in their expression pattern with the rest of the genes in the cell than expected from random, and have a tendency to be expressed in only a few tissues. Therefore, contrary to earlier hypotheses and our expectations, the vast majority of nonessential disease genes occupy functionally peripheral and topologically neutral positions in the cellular network. In stark contrast, essential genes are likely to encode hubs, show highly synchronized expression with the rest of the genes, and are expressed in most tissues, being overrepresented among housekeeping genes. Thus, essential genes are topologically and functionally central.</div>
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This unexpected peripherality of most disease genes can be best explained by using an evolutionary argument. Mutations in topologically central, widely expressed genes are more likely to result in severe impairment of normal developmental and/or physiological function, leading to lethality <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">in utero</em> or early extrauterine life and to eventual deletion from the population. Only mutations compatible with survival into the reproductive years are likely to be maintained in a population. Therefore, disease-related mutations in the functionally and topologically peripheral regions of the cell give a higher chance of viability.</div>
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Disease genes whose mutations are somatic should not be subject to the selective pressure discussed above. Instead, somatic mutations that lead to severe disease phenotypes should more likely affect the functional center. To test the predictive power of this selection-based argument, we studied separately the properties of somatic cancer genes (Cancer Genome Census; <a href="http://www.sanger.ac.uk/genetics/CGP/Census" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">www.sanger.ac.uk/genetics/CGP/Census</a>) and found that they (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">i</em>) are more likely to encode hubs, (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">ii</em>) show higher coexpression with the rest of the genes in the cell, and (<em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">iii</em>) are more represented among housekeeping genes (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 10</a>). The observed functional and topological centrality of somatic cancer genes fits well with our current understanding that many cancer genes play critical roles in cellular development and growth (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-11" id="xref-ref-11-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">11</a>).</div>
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<a class="prev-section-link" href="http://www.pnas.org/content/104/21/8685.full#sec-1" style="background-image: url(http://www.pnas.org/local/img/misc/arrow-blue-up.png); background-position: 0% 0%; background-repeat: no-repeat no-repeat; border: 0px; color: #0066a4; display: block; font-family: inherit; font-size: inherit; font-style: inherit; height: 15px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline; width: 13px;" title="Results"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; left: -9999px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; position: absolute; text-align: inherit; vertical-align: baseline;">Previous Section</span></a><a class="next-section-link" href="http://www.pnas.org/content/104/21/8685.full#ack-1" style="background-image: url(http://www.pnas.org/local/img/misc/arrow-blue-down.png); background-position: 0% 0%; background-repeat: no-repeat no-repeat; border: 0px; color: #0066a4; display: block; font-family: inherit; font-size: inherit; font-style: inherit; height: 15px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline; width: 13px;" title="Acknowledgments"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; left: -9999px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; position: absolute; text-align: inherit; vertical-align: baseline;">Next Section</span></a></div>
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Discussion</h2>
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Throughout history, clinicians and medical researchers have focused on a few disorder(s) sharing commonalities in etiology or pathology. Recent progress in genetics and genomics has led to an appreciation of the effects of gene mutations in virtually all disorders and provides the opportunity to study human diseases all at once rather than one at a time (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-4" id="xref-ref-4-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">4</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-30" id="xref-ref-30-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">30</a>). This unique approach offers the possibility of discerning general patterns and principles of human disease not readily apparent from the study of individual disorders.</div>
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An important tool in this quest is the HDN that represents a genome-wide roadmap for future studies on disease associations. The accompanying detailed diseasome map (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 13</a>), showing all disorders and the genes associated with different disorders, offers a rapid visual reference of the genetic links between disorders and disease genes, a valuable global perspective for physicians, genetic counselors, and biomedical researchers alike.</div>
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To test whether the conclusions obtained in this work are robust to the incompleteness of the OMIM coverage, we expanded our study to include not only genes with identified mutations linked to the specific disease phenotype, but also those that satisfy the less stringent criterion that the phenotype has not been mapped to a specific locus (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-18" id="xref-ref-18-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">18</a>). This expansion increased the number of disease-associated genes from 1,777 to 2,765, but also introduced noise in the data, because the link between many of the newly added genes and diseases is less stringent. Yet, the overall organization of the expanded diseasome map remains largely unaltered (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 11</a>), and none of the trends uncovered in <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F4" id="xref-fig-4-12" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 4</a> are affected by this extension (<a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 12</a>), supporting the robustness of our findings to further expansion of the OMIM database. Thus, although the maps shown in <a class="xref-fig" href="http://www.pnas.org/content/104/21/8685.full#F2" id="xref-fig-2-8" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">Fig. 2</a> and <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">SI Fig. 13</a> will inevitably undergo local changes with the discovery of new disease genes, this will not change the overall organization and layout of the HDN significantly, because the HDN reflects the underlying cellular network-based relationship between genes and functional modules.</div>
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Acknowledgments</h2>
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We thank Victor McKusick, Ada Hamosh, Joanna Amberger, and the rest of the OMIM team for their hard work and dedication and Tom Deisboeck, Zoltán Oltvai, Joanna Amberger, Todd Golub, Gerardo Jimenez-Sanchez and the members of the M.V. laboratory and the Center for Cancer Systems Biology, especially David E. Hill, for useful discussions. K.-I.G. and A.-L.B. were supported by National Institutes of Health (NIH) Grants IH U01 A1070499-01 and U56 CA113004 and National Science Foundation Grant ITR DMR-0926737 IIS-0513650. This work was supported by the Dana–Farber Cancer Institute (DFCI) Strategic Initiative (M.V.) and grants from the W. M. Keck Foundation (to M.V.) and the NIH/National Human Genome Research Institute and NIH/National Institute of General Medical Sciences (to M.V.).</div>
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Footnotes</h2>
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<li class="corresp" id="corresp-1" style="border-bottom-style: none; border-left-width: 0px; border-right-width: 0px; border-top-width: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 1px 0px; text-align: left; vertical-align: baseline; width: 648.84375px;">**To whom correspondence may be addressed. E-mail: <a href="mailto:alb@nd.edu" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">alb@nd.edu</a> or <a href="mailto:marc_vidal@dfci.harvard.edu" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">marc_vidal@dfci.harvard.edu</a></li>
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Author contributions: D.V., B.C., M.V., and A.-L.B. designed research; K.-I.G. and M.E.C. performed research; K.-I.G. and M.E.C. analyzed data; and K.-I.G., M.E.C., D.V., M.V., and A.-L.B. wrote the paper.</div>
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The authors declare no conflict of interest.</div>
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This article is a PNAS Direct Submission.</div>
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This article contains supporting information online at <a href="http://www.pnas.org/cgi/content/full/0701361104/DC1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">www.pnas.org/cgi/content/full/0701361104/DC1</a>.</div>
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<li class="glossary" id="glossary-1" style="border-bottom-style: none; border-left-width: 0px; border-right-width: 0px; border-top-width: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 1px 0px; text-align: left; vertical-align: baseline; width: 648.84375px;">Abbreviations:
<dl id="def-list-1" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.5em 0px; position: relative; text-align: inherit; vertical-align: baseline;">
<dt id="def-item-1" style="border: 0px; clear: left; float: left; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.2em 1em; text-align: inherit; vertical-align: baseline;">DGN,</dt>
<dd style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px 0px 0px 7em; outline-style: none; padding: 0.2em 1em; vertical-align: baseline;">disease gene network;</dd>
<dt id="def-item-2" style="border: 0px; clear: left; float: left; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.2em 1em; text-align: inherit; vertical-align: baseline;">HDN,</dt>
<dd style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px 0px 0px 7em; outline-style: none; padding: 0.2em 1em; vertical-align: baseline;">human disease network;</dd>
<dt id="def-item-3" style="border: 0px; clear: left; float: left; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.2em 1em; text-align: inherit; vertical-align: baseline;">GO,</dt>
<dd style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px 0px 0px 7em; outline-style: none; padding: 0.2em 1em; vertical-align: baseline;">Gene Ontology;</dd>
<dt id="def-item-4" style="border: 0px; clear: left; float: left; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.2em 1em; text-align: inherit; vertical-align: baseline;">OMIM,</dt>
<dd style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px 0px 0px 7em; outline-style: none; padding: 0.2em 1em; vertical-align: baseline;">Online Mendelian Inheritance in Man;</dd>
<dt id="def-item-5" style="border: 0px; clear: left; float: left; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0.2em 1em; text-align: inherit; vertical-align: baseline;">PCC,</dt>
<dd style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px 0px 0px 7em; outline-style: none; padding: 0.2em 1em; vertical-align: baseline;">Pearson correlation coefficient.</dd></dl>
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Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-78446564330824447082013-11-09T08:51:00.003-08:002013-11-09T08:51:32.857-08:00<span style="background-color: white; color: #202020; font-family: 'Open Sans', sans-serif; font-size: 24px; line-height: inherit;">The human disease network</span><br />
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<li id="contrib-1" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Kwang-Il+Goh&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Kwang-Il Goh</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-1" id="xref-aff-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">*</a> <span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-5" id="xref-aff-5-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">§</span> </a>, </li>
<li id="contrib-2" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Michael+E.+Cusick&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Michael E. Cusick</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-3" id="xref-aff-3-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">¶</span> </a>, </li>
<li id="contrib-3" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=David+Valle&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">David Valle</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-6" id="xref-aff-6-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‖</span> </a>, </li>
<li id="contrib-4" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Barton+Childs&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Barton Childs</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-6" id="xref-aff-6-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‖</span> </a>, </li>
<li id="contrib-5" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Marc+Vidal&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Marc Vidal</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-3" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-3" id="xref-aff-3-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">¶</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-corresp" href="http://www.pnas.org/content/104/21/8685.full#corresp-1" id="xref-corresp-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">**</a>, and </li>
<li id="contrib-6" style="border: 0px; display: inline; font-family: inherit; font-size: inherit; font-style: inherit; line-height: 1.7; list-style-position: outside; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;"><span class="name" style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;"><a class="name-search" href="http://www.pnas.org/search?author1=Albert-L%C3%A1szl%C3%B3+Barab%C3%A1si&sortspec=date&submit=Submit" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0px; white-space: nowrap;">Albert-László Barabási</a></span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-1" id="xref-aff-1-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">*</a> <span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-2" id="xref-aff-2-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">†</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-aff" href="http://www.pnas.org/content/104/21/8685.full#aff-4" id="xref-aff-4-4" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;"><span style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -0.6em; vertical-align: baseline;">‡</span> </a><span class="xref-sep" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: 0.6em;">,</span> <a class="xref-corresp" href="http://www.pnas.org/content/104/21/8685.full#corresp-1" id="xref-corresp-1-2" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: 0.2em;">**</a></li>
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<a href="http://www.pnas.org/content/104/21/8685.full#" style="background-image: url(http://www.pnas.org/local/img/misc/double-arrow-up.gif); background-position: 19% 50%; background-repeat: no-repeat no-repeat; border: 0px; color: #0066a4; display: block; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;" title="">Author Affiliations</a></div>
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Edited by H. Eugene Stanley, Boston University, Boston, MA, and approved April 3, 2007 (received for review February 14, 2007)</div>
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<h2 style="border: none; color: #202020; font-family: 'Open Sans', sans-serif !important; font-size: 24px; font-style: inherit; font-weight: normal; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: left; vertical-align: baseline;">
Abstract</h2>
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A network of disorders and disease genes linked by known disorder–gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.</div>
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<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=biological+networks&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">biological networks</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=complex+networks&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">complex networks</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=human+genetics&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">human genetics</a></span></li>
<li class="kwd" style="border-right-color: rgb(204, 204, 204); border-right-style: solid; border-width: 0px 1px 0px 0px; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=systems+biology&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">systems biology</a></span></li>
<li class="kwd" style="border: none; display: inline; font-family: inherit; font-size: 14px; font-style: inherit; font-weight: normal; line-height: 1.4; margin: 0px; outline-style: none; padding: 0.25em; vertical-align: baseline;"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px 3px 0px 0px; text-align: inherit; vertical-align: baseline; white-space: nowrap;"><a class="kwd-search" href="http://www.pnas.org/search?fulltext=diseasome&sortspec=date&submit=Submit&andorexactfulltext=phrase" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">diseasome</a></span></li>
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Decades-long efforts to map human disease loci, at first genetically and later physically (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-1" id="xref-ref-1-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">1</a>), followed by recent positional cloning of many disease genes (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-2" id="xref-ref-2-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">2</a>) and genome-wide association studies (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-3" id="xref-ref-3-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">3</a>), have generated an impressive list of disorder–gene association pairs (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-4" id="xref-ref-4-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">4</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-5" id="xref-ref-5-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">5</a>). In addition, recent efforts to map the protein–protein interactions in humans (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-6" id="xref-ref-6-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">6</a>, <a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-7" id="xref-ref-7-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">7</a>), together with efforts to curate an extensive map of human metabolism (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-8" id="xref-ref-8-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">8</a>) and regulatory networks offer increasingly detailed maps of the relationships between different disease genes. Most of the successful studies building on these new approaches have focused, however, on a single disease, using network-based tools to gain a better understanding of the relationship between the genes implicated in a selected disorder (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-9" id="xref-ref-9-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">9</a>).</div>
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Here we take a conceptually different approach, exploring whether human genetic disorders and the corresponding disease genes might be related to each other at a higher level of cellular and organismal organization. Support for the validity of this approach is provided by examples of genetic disorders that arise from mutations in more than a single gene (locus heterogeneity). For example, Zellweger syndrome is caused by mutations in any of at least 11 genes, all associated with peroxisome biogenesis (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-10" id="xref-ref-10-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">10</a>). Similarly, there are many examples of different mutations in the same gene (allelic heterogeneity) giving rise to phenotypes currently classified as different disorders. For example, mutations in <em style="border: 0px; font-family: inherit; font-size: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; vertical-align: baseline;">TP53</em> have been linked to 11 clinically distinguishable cancer-related disorders (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-11" id="xref-ref-11-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">11</a>). Given the highly interlinked internal organization of the cell (<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-12" id="xref-ref-12-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">12</a>–<a class="xref-bibr" href="http://www.pnas.org/content/104/21/8685.full#ref-17" id="xref-ref-17-1" style="border: 0px; color: #0066a4; font-family: inherit; font-size: inherit; font-style: inherit; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline;">17</a>), it should be possible to improve the single gene–single disorder approach by developing a conceptual framework to link systematically all genetic disorders (the human “disease phenome”) with the complete list of disease genes (the “disease genome”), resulting in a global view of the “diseasome,” the combined set of all known disorder/disease gene associations.<a class="prev-section-link" href="http://www.pnas.org/content/104/21/8685.full#abstract-1" style="background-image: url(http://www.pnas.org/local/img/misc/arrow-blue-up.png); background-position: 0% 0%; background-repeat: no-repeat no-repeat; border: 0px; color: #0066a4; display: inline !important; font-family: inherit; font-size: inherit; font-style: inherit; height: 15px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; text-align: inherit; text-decoration: none; vertical-align: baseline; width: 13px;" title="Abstract"><span style="border: 0px; font-family: inherit; font-size: inherit; font-style: inherit; left: -9999px; line-height: inherit; margin: 0px; outline-style: none; padding: 0px; position: absolute; text-align: inherit; vertical-align: baseline;">Previous Section</span></a></div>
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Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-16137673099312873832013-11-08T13:12:00.001-08:002013-11-08T13:12:15.768-08:00<div class="article-rel-wrapper">
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);">Determinazione Rara</span></span></h2>
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<span class="modifydate" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Last Updated on Friday, 18 October 2013 13:06</span></span><span class="createdby" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Written by Uniamo</span></span><span class="createdate" style="display: block;"><span style="background-color: rgba(255, 255, 255, 0);">Monday, 14 October 2013 18:18</span></span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">There are no translations available.</span></div>
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<strong style="background-color: rgba(255, 255, 255, 0);"><img align="right" alt="alt" src="http://www.uniamo.org/images/stories/news/diversity.jpg" style="text-align: start;" /></strong></div>
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<strong style="background-color: rgba(255, 255, 255, 0);"><strong>DETERMINAZIONE RARA</strong> è un progetto co-finanziato dal <strong>Ministero del Lavoro e delle Politiche Sociali</strong> e da <strong>UNIAMO F.I.M.R. onlus</strong> che sviluppa un <strong>nuovo importante percorso formativo</strong> di grande respiro e che prevede <strong>6 tappe</strong> (ciascuna di un giorno e mezzo), <strong>articolate in 3 sessioni</strong> principali, in calendario dall'<strong>8 novembre 2013 fino ad aprile 2014</strong> sulle nuove frontiere della ricerca.</strong></div>
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<span style="background-color: rgba(255, 255, 255, 0);"><strong>Partner</strong> attivi di questo percorso sono l'<strong>IRCCS Ospedale Bambino Gesù, Telethon, AIFA e Istituto Superiore di Sanità</strong>che, con la presenza di loro rappresentanti in aula, <strong>dialogheranno, discuteranno e si confronteranno direttamente con i partecipanti</strong> attraverso un percorso didattico interattivo, <strong>partendo da esperienze concrete</strong> di sperimentazione clinica e biobanking, da studi clinici in corso, da modelli di consenso informato in uso, sui nuovi confini aperti della ricerca biomedica.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">La <strong>partecipazione</strong> e la <strong>condivisione</strong> delle esperienze di ogni singola associazione non solo faranno la differenza ma renderanno concreto ed unico questo percorso di <em><strong>empowerment</strong></em> che, inoltre, metterà a disposizione di tutti i partecipanti<strong>uno spazio di lavoro interattivo digitale</strong> per condividere materiali, per discussioni e comunicazioni a distanza, mentre<strong>ognuna delle 6 tappe</strong> in cui si articola DETERMINAZIONE RARA <strong>offrirà dei vademecum di buona pratica</strong> della ricerca, dal biobanking ai farmaci off-label, all'anagrafica dell'associazione.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">L'obiettivo è quello di <strong>fornire degli strumenti utili a tutta l'associazione</strong> affinché i diretti partecipanti a DETERMINAZIONE RARA possano essere attivatori di curiosità e conoscenza all'interno della propria associazione e offrire possibilità di empowerment, e quindi di partecipazione informata e consapevole ai processi di cura e di ricerca, al maggior numero di persone possibile.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Il percorso offerto da <strong>Determinazione Rara permetterà una presenza competente e un ruolo attivo dei pazienti e dei loro rappresentanti nei processi della ricerca scientifica</strong> che li coinvolgono direttamente: sarà un cantiere di buone pratiche tra associazioni e professionisti della sperimentazione e della ricerca.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">I temi trattati nelle 3 principali sessioni andranno a toccare aree di grande importanza quali:</span></div>
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<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);"><strong>il ruolo attivo dei malati rari e delle loro associazioni nella valutazione, sviluppo e verifica della ricerca scientifica sulle malattie rare</strong>: la buona pratica del consenso informato, i comitati etici, le commissioni tecnico-scientifiche come strumenti per comprendere e agire attivamente il biobanking e la ricerca (Roma 8-9 novembre; 13-14 dicembre 2013);</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);"><strong>gli esiti della ricerca e il loro monitoraggio</strong>: gli scenari aperti dallo sviluppo di farmaci innovativi, i percorsi decisionali di accesso ai farmaci per malati rari, con particolare attenzione al processo MOCA - Mechanism of Coordinated Access to Orphan Drugs (Roma 10-11 gennaio; 7-8 febbraio 2014);</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);"><strong>i registri</strong>: informazioni di qualità per il miglioramento della ricerca e della cura.</span></li>
</ol>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">Si proporrà anche un applicativo web per la gestione delle anagrafiche delle associazioni, per un osservatorio associativo di qualità (Roma 28-29 marzo; 4-5 aprile 2014 ).</span></div>
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<strong style="background-color: rgba(255, 255, 255, 0);">Destinatari</strong></div>
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<span style="background-color: rgba(255, 255, 255, 0);"><strong>DETERMINAZIONE RARA è rivolto al mondo dell'associazionismo</strong> <strong>che si occupa di malattie rare</strong>: per agevolare l'interattività e la partecipazione, il numero massimo di partecipanti è di 25 persone.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">Ciascuna associazione può decidere se far partecipare all'intero percorso un unico rappresentante, oppure se iscrivere 3 persone che seguiranno ciascuna una sessione.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">E' consigliabile garantire la costanza nella partecipazione.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">Nel caso pervenga un alto numero di iscrizioni, la priorità verrà data, in ordine:</span></div>
<ol>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">ai soci di associazioni affiliate: costituisce titolo preferenziale l'aver frequentato altri percorsi formativi promossi dalla Federazione;</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">ai soci di associazioni non affiliate, con priorità per coloro che hanno già partecipato ad altri percorsi formativi promossi dalla Federazione.</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">a candidati singoli;</span></li>
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<span style="background-color: rgba(255, 255, 255, 0);">Inoltre, chi volesse aderire solamente ad una singola sessione, potrà avanzare la propria candidatura in qualità di uditore alla Segreteria Uniamo Firm Onlus, specificando le ragioni della sua scelta: si valuterà se accogliere la richiesta, nel limite massimo di 2 uditori per sessione.</span></div>
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<strong style="background-color: rgba(255, 255, 255, 0);">Costi</strong></div>
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<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">Il costo di compartecipazione per l'intero percorso a carico dell'associazione federata è di <strong>100 euro</strong>; la Federazione UNIAMO F.I.M.R. onlus garantisce la copertura delle spese alberghiere.</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">Se ci sarà la copertura economica, alla fine del percorso si potrà riconoscere un "bonus" a chi avrà frequentato con regolarità.</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">Il costo di compartecipazione per l'intero percorso a carico dell'associazione non federata è di <strong>200 euro</strong>.</span></li>
<li style="text-align: start;"><span style="background-color: rgba(255, 255, 255, 0);">Il costo di compartecipazione per l'intero percorso a carico del singolo partecipante è di <strong>200 euro</strong>.</span></li>
</ul>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">Le <strong>iscrizioni</strong> dovranno pervenire alla Segreteria di Uniamo Fimr Onlus a <strong>mezzo fax 041-2410886</strong> o via e-mail a <a href="mailto:segreteria@uniamo.org" style="text-decoration: none;">segreteria@uniamo.org</a> , <strong>entro e non oltre il 25 ottobre 2013</strong>. Le coordinate bancarie per il pagamento verranno fornite all'atto della conferma di iscrizione.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px; text-align: start;">
<span style="background-color: rgba(255, 255, 255, 0);">In allegato la sintesi programma del corso e la scheda di iscrizione.</span></div>
<div style="margin-bottom: 15px; margin-top: 10px;">
<br /></div>
<div class="attachmentsList" style="-webkit-text-size-adjust: auto; background-color: white; font-family: Helvetica, Arial, sans-serif; font-size: 12px; line-height: 16px;">
<table style="background-color: transparent; border: 0px; margin-top: 10px;"><caption style="font-weight: bold; margin-top: 4px; text-align: left;"><span style="font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);">Attachments:</span></span></caption><tbody>
<tr class="odd"><td class="at_filename" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; vertical-align: top;"><span style="color: black; font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);"><a class="at_icon" href="http://www.uniamo.org/attachments/575_DR_programma_definitivo.pdf" style="font-weight: bold; padding-right: 4px; text-decoration: none;" title="Download this file (DR_programma_definitivo.pdf)"><img alt="Download this file (DR_programma_definitivo.pdf)" src="http://www.uniamo.org/components/com_attachments/media/icons/pdf.gif" style="border: 0px; vertical-align: text-bottom;" /></a><a class="at_url" href="http://www.uniamo.org/attachments/575_DR_programma_definitivo.pdf" style="font-weight: bold; margin-left: 5px; margin-right: 30px; text-decoration: none;" title="Download this file (DR_programma_definitivo.pdf)">Programma Determinazione Rara def</a></span></span></td><td class="at_file_size" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; text-align: right; vertical-align: top;"><span style="font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);">557 Kb</span></span></td></tr>
<tr class="even"><td class="at_filename" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; vertical-align: top;"><span style="color: black; font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);"><a class="at_icon" href="http://www.uniamo.org/attachments/575_Scheda%20Determinazione%20Rara.doc" style="font-weight: bold; padding-right: 4px; text-decoration: none;" title="Download this file (Scheda Determinazione Rara.doc)"><img alt="Download this file (Scheda Determinazione Rara.doc)" src="http://www.uniamo.org/components/com_attachments/media/icons/word.gif" style="border: 0px; vertical-align: text-bottom;" /></a><a class="at_url" href="http://www.uniamo.org/attachments/575_Scheda%20Determinazione%20Rara.doc" style="font-weight: bold; margin-left: 5px; margin-right: 30px; text-decoration: none;" title="Download this file (Scheda Determinazione Rara.doc)">Scheda Determinazione Rara.doc</a></span></span></td><td class="at_file_size" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; text-align: right; vertical-align: top;"><span style="font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);">94 Kb</span></span></td></tr>
<tr class="odd" style="background-color: transparent;"><td class="at_filename" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; vertical-align: top;"><span style="color: black; font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);"><a class="at_icon" href="http://www.uniamo.org/attachments/575_DETERMINAZIONE%20RARA_SCHEDA%20RACCOLTA%20QUESITI_MODULO%201_comitati%20etici.doc" style="font-weight: bold; padding-right: 4px; text-decoration: none;" title="Download this file (DETERMINAZIONE RARA_SCHEDA RACCOLTA QUESITI_MODULO 1_comitati etici.doc)"><img alt="Download this file (DETERMINAZIONE RARA_SCHEDA RACCOLTA QUESITI_MODULO 1_comitati etici.doc)" src="http://www.uniamo.org/components/com_attachments/media/icons/word.gif" style="border: 0px; vertical-align: text-bottom;" /></a><a class="at_url" href="http://www.uniamo.org/attachments/575_DETERMINAZIONE%20RARA_SCHEDA%20RACCOLTA%20QUESITI_MODULO%201_comitati%20etici.doc" style="font-weight: bold; margin-left: 5px; margin-right: 30px; text-decoration: none;" title="Download this file (DETERMINAZIONE RARA_SCHEDA RACCOLTA QUESITI_MODULO 1_comitati etici.doc)">DR Scheda Raccolta Quesiti mod.1</a></span></span></td><td class="at_file_size" style="padding-bottom: 4px; padding-left: 3px; padding-right: 3px; text-align: right; vertical-align: top;"><span style="font-family: Times;"><span style="-webkit-text-size-adjust: none; background-color: rgba(255, 255, 255, 0);">88 Kb</span></span><br /></td></tr>
</tbody></table>
</div>
Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-474396893593033662013-10-12T12:59:00.001-07:002013-10-12T12:59:15.005-07:00OSTEOMIELITE CRONICA MULTIFOCALE RICORRENTE: ho inserito un nuovo link sotto la voce "link util...<a href="http://ocmr.blogspot.com/2013/10/ho-inserito-un-nuovo-link-sotto-la-voce.html?spref=bl">OSTEOMIELITE CRONICA MULTIFOCALE RICORRENTE: ho inserito un nuovo link sotto la voce "link util...</a>: ho inserito un nuovo link sotto la voce "link utili" AIFP ASSOCIAZIONE ITALIANA FEBBRI PERIODICHE http://www.febbriperiodiche...Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-16128443499239415912013-10-12T12:58:00.001-07:002013-10-12T12:58:13.771-07:00OSTEOMIELITE CRONICA MULTIFOCALE RICORRENTE: Vi suggerisco un link in cui potete trovare divers...<a href="http://ocmr.blogspot.com/2013/10/vi-suggerisco-un-link-in-cui-potete.html?spref=bl">OSTEOMIELITE CRONICA MULTIFOCALE RICORRENTE: Vi suggerisco un link in cui potete trovare divers...</a>: Vi suggerisco un link in cui potete trovare diverse pubblicazioni sulla OCMR http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=DetailsS...Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0tag:blogger.com,1999:blog-6684601906212672304.post-53406500878971688702013-10-12T12:55:00.000-07:002013-10-12T12:55:04.746-07:00Vi suggerisco un link in cui potete trovare diverse pubblicazioni sulla OCMR<br />
<br />
<a href="http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=DetailsSearch&Term=chronic%5Bti%5D+recurren*%5Bti%5D+osteomyelitis+OR+(chronic+recurrent+multifocal+osteomyelitis%5Btw%5D)">http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=DetailsSearch&Term=chronic%5Bti%5D+recurren*%5Bti%5D+osteomyelitis+OR+(chronic+recurrent+multifocal+osteomyelitis%5Btw%5D)</a>Anonymoushttp://www.blogger.com/profile/17982693014840834522noreply@blogger.com0