A Machine Learning Approach for Identifying Amino Acid Signatures in the HIV Env Gene Predictive of Dementia 英文参考文献.docVIP

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A Machine Learning Approach for Identifying Amino Acid Signatures in the HIV Env Gene Predictive of Dementia 英文参考文献.doc

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A Machine Learning Approach for Identifying Amino Acid Signatures in the HIV Env Gene Predictive of Dementia 英文参考文献

AMachineLearningApproachforIdentifyingAmino AcidSignaturesintheHIVEnvGenePredictiveof Dementia AlexanderG.Holman1,DanaGabuzda1,2* 1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 2Department of Neurology (Microbiology,andImmunobiology),HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Theidentificationofnucleotidesequencevariationsinviralpathogenslinkedtodiseaseandclinicaloutcomesisimportant fordevelopingvaccinesandtherapies.However,identifyingthesegeneticvariationsinrapidlyevolvingpathogensadapting toselectionpressuresuniquetoeachhostpresentsseveralchallenges.Machinelearningtoolsprovidenewopportunitiesto address these challenges. In HIV infection, virus replicating within the brain causes HIV-associated dementia (HAD) and milderformsofneurocognitiveimpairmentin20–30%ofpatientswithunsuppressedviremia.HIVneurotropismisprimarily determinedbytheviralenvelope(env)gene.ToidentifyaminoacidsignaturesintheHIVenvgenepredictiveofHAD,we developed amachine learning pipeline using the PART rule-learning algorithm andC4.5 decision tree inducer to train a classifieronameta-dataset(n=860envsequencesfrom78patients:40HAD,38non-HAD).Toincreasetheflexibilityand biologicalrelevanceofouranalysis,weincluded4numericfactorsdescribingaminoacidhydrophobicity,polarity,bulkiness, andcharge,inadditiontoaminoacididentities.Theclassifierhad75%predictiveaccuracyinleave-one-outcross-validation, andidentified5signaturesassociatedwithHADdiagnosis(p,0.05,Fisher’sexacttest).TheseHADsignatureswerefoundin themajorityofbrainsequences from8of10HADpatientsfromanindependentcohort.Additionally,2HADsignatures werevalidatedagainstenvsequencesfromCSFofasecondindependentcohort.Thisanalysisprovidesinsightintoviral geneticdeterminantsassociatedwithHAD,anddevelopsnovelmethodsforapplyingmachinelearningtoolstoanalyzethe geneticsofrapidlyevolvingpathogens. Citation:HolmanAG,GabuzdaD(2012)AMachineLearningApproachforIdenti