Theseslideswerepresentedath/ps://www.pmwcintl.com/cur7s-bagne-2018mich/.
Youwilllearnhowtomakedrugdevelopmentmorescien7fic,precise,ethical,produc7ve,andlesscostly.
Otherpresentersatthismee7ngaredriversofprecisiondrugdevelopment.TheseincludeLeeHoodrepresen7ngsystemsbiologyandP4Medicine,FrancisCollinsrepresen7ngmoderngenomics,andEricTopolrepresen7ngthescienceofindividualityinhisbook,TheCrea(veDestruc(onofMedicine.
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Prevailingrandomizedcontrolledtrialdesigns,da7ngbackto1948,wereanimportantscien7ficadvance.However,RCTdesignscomplianttoCONSORT,FDAguidelines,andPCORIMethodologyStandardsdohavefundamentalproblemsandlimita7ons.Amongtheseareconfoundingtreatmenteffectswitheffectsofindividualdifferences,includinggene7cdifferences.Eachpa7entcouldbeadifferentconfoundedmixofac7vetreatmentandindividualdifferencesresponse.Genomicsaccentuatesindividualdifferences.CurrentRCTdesignsaveragethemout.Homogenizingpersonsisan7the7caltogenomics.
Stra7fica7onhelps.However,therearemorecombina7onsofindividualdifferences,typesoftreatment,anddosesoftreatmentthantherearepersonintheworld.Youwilllearnhowtosolvethisproblemwithmorerandomiza7onandSIMA.
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PrevailingRCTdesignsalsoconfoundtrueresponderstoac1vetreatmentwithrespondersonac1vetreatmentthatwouldhaverespondedtoplacebo.Eachpa7entcouldbeadifferentconfoundedmixofac7vetreatmentandplaceboresponse.
Inaddi7on,classical-designRCTsthatfocusonefficacyneglectsafety,precludedoseop7miza7onforindividualpa7ents,arenotwellsuitedtoaccountfordelayandpersistenceofresponse,anddonotcapitalizeonmoderndatacollec7onandprocessingcapabili7es.Youwilllearnhowtoaddresssuchproblemsasaset.
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Confoundingcontributesto“imprecisionmedicine”asquan7fiedbyNikSchorkinNature.Hereareresultsfor10top-grossingdrugs.Thebluepersonsarehelped.Theredpersonsarenot.Imprecisiondrivesupcostsandcloudsiden7fica7onofgene7candotherpredictorsofdifferen7aldrugresponse.
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DrugdevelopmentwithSIMAcanbesimpler,morescien7fic,andmoreprecisebymeasuringthebenefitsandharmsoftreatment.Measurementofbenefitandharmreducesthedimensionalityoftreatmentevalua7onproblems.
Randomizedcontrolledtrialscanprovidecanprovideaccurateandintegratedevalua7onsofsafetyandeffec7venessforeachperson.
Rejec7onofthenullhypothesistotherightindicatesthatbenefitsexceedharms.Rejec7onofthenullhypothesistotheleaindicatesthatharmsexceedbenefits.
Inaddi7on,SIMAprovidesscoresthatcanbeaggregatedandanalyzedsta7s7callyforpopula7onmedicine.
Thisapproachwouldhelpobviatetheclinicalresearchtoclinicalprac7cetransla7onbo/leneck.
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SIMAisatooltoacceleratebasicandappliedsciencesofcomplexadap7vesystems.
SIMAmeasuresinterac7onsover7methatdescribeandhelppredicthowCASworkover7me.
SIMAquan7fiesedgesinnetworkgraphswheneachnodeisa7meseries.
SIMAcanbeanAItool.
TodayIfocusonmeasurementofbenefitandharmforresponse.
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Thisisasetofthreesingle-personRCTsthatusethesametypeofdrug,thesamesetoffourdosesincludingplacebo,andthesamethreeresponsevariables.Thesearemockdatafora16weektrialwith4pairsof2-weekperiods.
Fourdoses,includingplaceboaszero-dose,wererandomizedover7meforeachofthreepa7ents.Within-personrandomiza1onofdoseseliminatesbothtypesofconfoundingshownbefore.CONSORT-compliantRCTsdonotrandomizeenough.Seethatdoseisinves1gatedasa1me-dependentdimensionalvariable,NOTacategoricalvariable.
Thissmall-scaleexamplehasonlythreeresponsevariables.Ideally,useenoughsafetyandeffec7venessresponsevariablestoobtaincomprehensiveevalua7onsofsafetyandeffec7veness.
TheseInterac7on-over-Timescores,computedbySIMA,quan7fytheamountofevidenceforinterac1onsover1me.Posi7veIoTscoresquan7fyhigherdoseswithhigherresponsevariablelevels.Nega7veIoTscoresquan7fyhigherdoseswithlowerresponsevariablelevels.
Userssettowardanduntowarddirec7oninaccordwithclinicalsignificanceandpa7entpreferences.Herehigherbloodpressureisuntoward.
Herearetheninebenefitandharmscoresinbagnez-scoreunits,threeforeachpa7ent.
Weightsalsoaresetintermsofclinicalsignificanceandpa7entpreferences.
OverallBenefitandHarmScoresareweightedaveragesforindividualpersons.
Nowcomessta7s7csaaerSIMA.Thenullhypothesisofnooverallbenefitandharmwasrejectedintheposi7veorbeneficialdirec7onwithatwo-tailedt-testonmeanoverallbenefitandharmscore.
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Thisisfromacomputersimula7onthatprocesseddifferentpor7onsofadatasetcreatedbyaddingwhitenoise–randomnormaldeviates–toagivensignal.Halfoftherepeatedmeasurementswereontreatmentandhalfoff.
SeehowsignificancelevelsincreasewiththenumberofsubjectsasexpectedusingchangescoresandwithoutSIMA.
AlsoseehowsignificancelevelsincreasewithnumberofrepeatedmeasurementsandSIMA.
Usingmorerepeatsisbe/erwhenonewantstoavoidconfoundingtheeffectsofindividualdifferenceswithtreatmenteffects,whenmorerepeatsarelessexpensivethanmoresubjects,andforraredisorders.Moredisordersarebecomingrareasdiagnos7cspecificityincreases.ThecurrentversionofSIMAsoawarecanprocessupto500repeatedmeasurements.
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Thisshowshowyoucoulddrilldownfromthesta7s7callysignificantdemonstra7onresulttoiden7fytheop7malminimumdoseacrossresponsevariablesforeachperson.
SIMAenablesrandomized7tra7ontoop7maldoseforeachperson.
Seehowtheseop7malminimumdosesare40,80,and20forpersons1,2,and3respec7vely.
Seehowthegroup-averageresultcloudstheperson-specificresults.
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Thecorrectanswersareinbold.
ThishelpsshowhowSIMAandsta7s7csaretwodis7nctandoaencomplementarymethodsthatdoapplytodifferenttypesofdataanddodifferentthings.
Precisiondrugdevelopmentandmedicineneedbothquan7ta7vemethods.
Deathisarealendpoint.Bloodpressureisnot.CONSORT-compliantRCTsoaenalsoconfoundrealendpointswithar7ficialendpoints.
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SIMAhelpsenabletrulypa7ent-centeredcompara1vesafetyANDeffec1venessresearch.
Increasingnumbersofdrugsmeanthatmoretreatmentsneedtobecompared.
Followthiswithasingle-samplet-testforeachtypeoftreatmenttoseeifeithertreatmentisbeneficialorharmful.
SIMAcangreatlysimplifysta7s7calanalyses.
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Ourna7onalmo/oisEpluribusunum–Outofmany,one.Thisslideisaboutestablishingthescienceofindividuality,Eunumpluribusandatwo-waystreetbetweenindividuals(SIMA)andpopula7ons(sta7s7cs).
You’vealreadyseenhowthe3-persondemonstra7onyieldedasta7s7callysignificantresult.Thatrepresentsgeneraliza7onatthetopofthepyramid.
Yousawthegroupaverageoverallbenefitandharmscore,thesecondleveldown.
YoualsosawhowSIMAquan7fiedoverallbenefitandharmasnonlinearfunc7onsofdoseforeachpersonfromtheresponsevariablespecificdose-responserela7onships.Thisrepresentswithin-personsummariza7on.Theseweredifferen7allyweightedandaveragedforthegroupofthreepersons–thesecondleveldown.
Yousawtheresponse-variable-specificbenefitandharmscoresforeachperson.Suchdetailedresultsillustratethescienceofindividuality.
Inaddi7on,SIMAcanquan7fybenefitandharmasnonlinearfunc7onsofresponsevariablelevel,delayandpersistenceofresponse,etc.SIMAcanusede-trendingtodis7nguishtreatmenteffectsfordiseaseprogressionandspontaneousrecovery.SIMAcanuseBooleanindependenteventsfordrug-druginterac7onsanddrugcocktails.SIMAcanuseBooleandependenteventsforsyndromessuchasmetabolicsyndromeanddepression.SIMAcanquan7fymechanismsofdiseaseandtreatmenteffect.SIMAcanhelpquan7fyevidenceforcausalitywithinpersonsorotherindividuals.
Thisapproachhaspoten7altoacceleratebothhighlypa7ent-centricprecisionmedicineandpopula7onmedicine.
Thisapproachcanhelpobviatetheclinicalresearchtoclinicalprac7cetransla7onproblemwithbothdrugsandservices.
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Eroom’slawstatesthatpharmaceu7calindustryproduc7vityhalvedaboutevery9½yearsininfla7on-adjusted$despitealltheinterveningscien7ficandtechnicaladvances.
Coulditbethattheregulatorysciencegatewayisbo/leneckedbyclinicaltrialsthatusecategoricalindependentvariablesandgroupaveragesatendpoints?
Mightweneedtoknowindividualswellthroughthescienceofindividualitybeforewecanclassifythemwell?
Clinicianstreatindividuals.Mightthescienceofindividuality,enabledbyapplyingSIMAtomul7variate7meseriesdata,betheheretoforemissingfounda1onformuchofevidence-basedprecisiondrugdevelopmentandmedicine?
MightthisapproachhelpreverseEroom’slaw?
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Yousaw,albeitwithmockdata,howitmightbepossibletoachievesta7s7callysignificantresultsinrandomizedsingle-groupRCTswithsmallnumbersofpersons.
Mightitbepossibletolargelyendclinicaldrugsafetyproblems?
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WithSIMA,drugdevelopmentbecomesmorelikeusingafunnellargeendup.SIMAhelpsprovideinforma7onneededtotargettherightdrugattherightdosetotherightperson.
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Genomicsismilesaheadofphenomics.Wholegenomesequencingisbecomingfeasibleformany.However,weares7llusingoutmodeddiseaseclassifica7onsandconfoundedcategoriesofresponderandnon-responder.
Thisproblemcanbelikenedtotryingtonailphenomicjellytoawallwithgene7cnails.
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Thisslideemphasizesmechanisms.Mechanismsandresponsetake7me.SIMAcomputes7me-dependentmechanism-specificphenotypesfrommul7variate7meseriesdata.
Thesethreecategories–diagnos7c,treatmentresponse,andagency–aredis7nguishedbyhow7meseriesinternalorexternaltotheindividualareselectedtooperateasindependentanddependentvariableswhenapplyingSIMA.
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