On Modeling HIV and T Cells In Vivo Assessing Causal Estimators in Vaccine Trials 英文参考文献.docVIP

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On Modeling HIV and T Cells In Vivo Assessing Causal Estimators in Vaccine Trials 英文参考文献.doc

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On Modeling HIV and T Cells In Vivo Assessing Causal Estimators in Vaccine Trials 英文参考文献

OnModelingHIVandTCellsInVivo: AssessingCausalEstimatorsinVaccineTrials W. David Wick*,Peter B.Gilbert, Steven G.Self StatisticalCenterforHIVandAIDSResearchandPrevention,FredHutchinsonCancerResearchCenter,Seattle,Washington,UnitedStatesofAmerica Thefirstefficacytrials—namedSTEP—ofaTcellvaccineagainstHIV/AIDSbeganin2004.Theunprecedentedstructure of these trials raised new modeling and statistical challenges. Is it plausible that memory T cells, as opposed to antibodies,canactuallypreventinfection?Iftheyfailatprevention,towhatextentcantheyamelioratedisease?And howdoweestimateefficacyinavaccinetrialwithtwoprimaryendpoints,onetraditional,oneentirelynovel(viralload afterinfection), andwherethelatter maybeinfluenced byselection biasdueto theformer?In preparationfor the STEPtrials,biostatisticiansdevelopednoveltechniquesforestimatingacausaleffectofavaccineonviralload,while accountingforpost-randomizationselectionbias.Butthesetechniqueshavenotbeentestedinbiologicallyplausible scenarios.WeintroducenewstochasticmodelsofTcellandHIVkinetics,makinguseofnewestimatesoftheratethat cytotoxicTlymphocytes—CTLs;theso-calledkillerTcells—cankillHIV-infectedcells.Basedonthesemodels,wemake the surprising discovery that it is not entirely implausible that HIV-specific CTLs might prevent infection—as the designersexplicitlyacknowledgedwhentheychosetheendpointsoftheSTEPtrials.Bysimulatingthousandsoftrials, wedemonstratethatthenewstatisticalmethodscancorrectlyidentifyanefficaciousvaccine,whileprotectingagainst afalseconclusionthatthevaccineexacerbatesdisease.Inadditiontouncoveringasurprisingimmunologicalscenario, ourresultsillustratetheutilityofmechanisticmodelinginbiostatistics. Citation:WickWD,GilbertPB,SelfSG(2006)OnmodelingHIVandTcellsinvivo:Assessingcausalestimatorsinvaccinetrials.PLoSComputBiol2(6):e64.DOI:10.1371/ journal.pcbi.0020064 measured in blood drawn sometime after the primary stage (and expressed as virions per milliliter, for example). Even Introduction The ?rst generatio