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Gregory House er hovedpersonen, der sammen med sit team af læger, forsøger at diagnosticere patienter ud fra deres oftest kryptiske kombinationer af symptomer. Dette sker igennem den såkaldte differentialdiagnosticering, hvor det bliver forsøgt at finde en diagnose ved, at undersøge om der er grundlag for sygdomme der passer på disse symptomer, og endvidere bruge udelukkelsesmetoden til at påvise denne diagnose
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