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ReportontheCaliforniaInitiativetoAdvancePrecisionMedicineTotheCaliforniaLegislatureJanuary2019

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CaliforniaInitiativetoAdvancePrecisionMedicineReportCaliforniaLegislatureJanuary2019ReportpreparedbytheGovernor’sOfficeofPlanningandResearchElizabethBaca,MD,MPADeputyDirector,Governor’sOfficeofPlanningandResearchSpecialacknowledgementsfortheirassistanceinpreparingthisreport:AtulButte,MD,PhDandIndiaHook-Barnard,PhD,atUniversityofCalifornia,SanFranciscoDavidR.Paquette,PhDandBenjaminRubin,PhD,ScienceOfficersfortheCaliforniaInitiativetoAdvancePrecisionMedicineGovernor’sOfficeofPlanningandResearch 1400TenthStreetSacramento,California95814Phone:(916)322-2318

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TableofContents

EXECUTIVESUMMARY 4

BACKGROUND 5

WHATIS“PRECISIONMEDICINE?” 5BRIEFHISTORYOFCIAPM:2015-2018 5

CIAPMALLOCATIONOFFUNDS 5

ALLOCATIONOFFUNDSFROMFY2016-17 5ALLOCATIONOFFUNDSFROMFY2017-18 6

PROGRAMHIGHLIGHTS 6

DEMONSTRATIONPROJECTS 6PROJECTSSTARTEDIN2015 6PROJECTSSTARTEDIN2017 11

CALIFORNIA’SNATIONALANDINTERNATIONALIMPACT 19

GOVERNOR’SPRECISIONMEDICINEADVISORYCOMMITTEE 20

NEXTSTEPSFORPRECISIONMEDICINE 21

CONCLUSION 21

APPENDIX1:PRESENTATIONSFROMDEMONSTRATIONPROJECTSIN2018 22

APPENDIX2:PUBLICATIONSFROMDEMONSTRATIONPROJECTSIN2018 25

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ExecutiveSummaryThe California Initiative to Advance Precision Medicine (CIAPM), administered by theGovernor’sOfficeofPlanningandResearch(OPR),hascontinuedtosupportinnovativeprojectsin precision health and medicine. Launched by the State in 2015 with $3 million in statefunding,CIAPMhasgrownintoa$53millionstateinitiative—theonlystate-runprogramofitskind nationwide. The program has continued to mature. In addition to proof of conceptdemonstration projects, OPR has started to bring together additional expertise to create apolicyframeworktosupportprecisionhealthandmedicine.Thelastyearhadseveralnotableachievements.2018MajorMilestones:

• Theoriginaleightstatefundeddemonstrationprojectshavecompletedtheirworkandwillnowundergoaformalevaluation

• Multiple projects have already published in peer-reviewed journals, changing thepracticeandthoughtaroundprecisionhealthandmedicineinterventions

• At leastoneprojecthassecureda licensingagreementtousetheir technology, taking

theprojectbeyondanacademiccenterandintothebroaderpatientcarearena

• A new request for proposals was issued to fund precision medicine approaches forcancer care, specifically addressing health disparities and ways to decrease themthroughprecisionapproaches

• The Governor appointed the Precision Medicine Advisory Committee which issued

“PrecisionMedicine:AnActionPlan forCalifornia,” a full report onpolicy actions thestate, legislature, and partners can take to further support precision health andmedicine

This report provides an update and builds on previous legislative reports for activities inCalifornia.

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Background

Whatis“PrecisionMedicine?”Precisionmedicine,alsoreferredtoasprecisionhealth,isanemergingfieldthatleveragesthevastamountsofgrowinghealthandotherdatatobetterprevent,predict,diagnosis,andtreatindividuals. There are several definitions across academic institutions as well as differentdefinitionsbynationalandinternationalprograms.TheCaliforniadefinitionis:

Precisionmedicineisdefinedasanapproachthataimstouseadvancedcomputingtoolsto aggregate, integrate and analyze vast amounts of data from research, clinical,personal,environmentalandpopulationhealthsettings,tobetterunderstandhealthanddisease, and to develop and deliver more precise diagnostics, therapeutics, andpreventionmeasures.

BriefHistoryofCIAPM:2015-2018Manycountries,includingtheUnitedStateshaverecognizedandlaunchedprecisionmedicineinitiatives. California continues to be the only statewide program in the country. OPRadministersandoverseesCIAPM.Theprogramwasinitiallylaunchedin2015with$3millionoffundingandsincethattimehasgrowntremendouslyto$53million.TheprogramisestablishedinstatutewithinOPRtodoanumberoffunctionsnotlimitedtobutincluding:

• Develop,implement,andevaluatedemonstrationprojects• Collaboratewithpublic,nonprofit,andprivateentities• Select projects that have a number of intended benefits for Californians including

reducingdisparities,havenear-termpositivehealthbenefits,elicitdataunderstanding,helpwithsysteminteroperability,andmanymore

• Developmetricsandmonitorthedemonstrationprojects• Solicitpublic,nonprofit,andprivatesectorinputforadditionalguidelines• Provideupdatestothelegislature

Previous CIAPM legislative reports provide additional background and context.1 This reportprovidesupdatesonactiveissuesforprecisionmedicine.

CIAPMAllocationofFunds

AllocationofFundsfromFY2016-17All of FY 2016-17 funds have been awarded and contracted. The projects have continued toconductwork,andasofDecember2018,haveallcometocompletion.SeeProgramhighlightsbelowforadditionaldetails.

1Availableat:http://opr.ca.gov/health/

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AllocationofFundsfromFY2017-18Theinitialprojectsawardedthroughacompetitive-peerreviewedprocesswereacrossavarietyofdiseaseareasfromcancertoheartdiseasetomultiplesclerosis.FortheFY2017-18funds,therequestforproposalwasfocusedonasinglediseasearea–cancer–andinformedbybroadexpertstakeholderengagementfocusedonthepotentialforprecisionmedicineapproachestoreducehealthdisparities.The request forproposals (RFP)was initiated in July2018.TheRFPprocessiscurrentlyunderway.

ProgramHighlights

DemonstrationProjectsCIAPM'sportfolioofdemonstrationprojectscoversabreadthofdiseaseareasandinstitutionsacross California. Together, the projects have established meaningful partnerships, withuniversities and research hospitals, companies, patient advocacy groups and institutions.Overall, more than 50 unique public and private entities are involved in the demonstrationprojects. Teams have continued to seek funding and support beyond the state precisionmedicinefunding.Theprojectsarenotonlycontributing tomedical science,health,andpreventionefforts,buttheyarealsoservingasplatformstobetterunderstandtheprogramandpolicyneedsfromaregulatory,patientengagement,economic,educational,andsystemschangeperspective.Theprogram leads are both presenting at national and international conferences as well assubmittingpublicationstohelpadvancethefield(seeAppendix1andAppendix2).Abriefdescriptionandhigh-levelaccomplishmentsoftheeightprojectsarebelow.Someoftheinformation is repeated from the January 2018 legislative report verbatim to providebackgroundandcontextwithadditionaltextforupdate.Asmentioned,theprojectscompletedtheirterminDecember2018,andwillundergoaformalexternalevaluationwithforthcomingreportstothelegislature.Demonstrationprojectsarelistedinalphabeticorderbytitle.Partnerinstitutionsare listed inalphabeticalorder.Newpartnersaddedafter initial launcharenotedwith*.

Projectsstartedin20151.CaliforniaKidsCancerComparison(CKCC)PrincipalInvestigator:DavidHaussler,UCSantaCruzPartnerinstitutionsResearchhospitalsforwhichUCSantaCruzprovidedanalysisinrealtimeforkidsintreatment:BritishColumbiaCancerAgency*Children’sHospitalOrangeCountyPacificPediatricNeuro-OncologyConsortium(UCSF)

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StanfordUniversityResearchhospitalswithwhichCKCCsharedanalysisandpipelineinformation:Children’sMercyHospitalinKansasCity*SanfordUniversityofSouthDakotaMedicalCenter*UniversityofMichigan,UniversityofPittsburg*AdvocacyorganizationswithwhichCKCCworkstomonitorfamilyandpatientneeds,andassistadvocacyaims:Alex’sLemonadeStandFoundationAmazonServicesAzureJacob’sHeartKeyforaCure*KidsvCancerLiveForOthersFoundation*St.Baldrick’sFoundation*TeamFinnTeamGFoundationUnravelPediatricCancerCommercialandindustrycompanieswithwhichCKCChaspartneredonsequencingplatforms,geneanalysis,andcloudservices:DNAnexusMicrosoft*NuMediiSevenBridgesFundingLaunched in October 2015, with $1.2 million in CIAPM state funds. CKCC completed theiroriginalgrantworkinApril2017butshortlythereafterwasawardedsupplementalfundingof$490,533under“CIAPMLimitedCompetitionforSupplementalFunds:RequestforProposals”tocontinuetheirworkuntilDecember2018.The UCSC team has leveraged CKCC support to gain additional funding from other fundingagencies, including St. Baldrick’s Foundation for a 5-year grant of $2.5 million, Team GFoundation at $30,000, and Unravel Foundation at $90,000. They have obtained matchingfundingcommitmentsfromLiveforOthersFoundationat$50,000,KeyforaCureFoundationat$150,000,andlocalphilanthropists,includingGeorgeandRafeKrawat$50,000,creatorsoftheKrawLectureSeriesonScienceandTechnology.TheCKCC team is currently indiscussion forotherfundstoestablishafellowshipinbigdatacomputingattheGenomicsInstitutethatwillbededicatedtopediatriccanceranalysis.

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ProjectThe CKCC Treehouse-Stanford Clinical Registry is a collaboration between UC Santa CruzGenomics Institute and Stanford University. The goal is to study the clinical utility ofcomparativegeneexpressionanalysisforchildrensufferingfrompediatriccancerandforwhomno standard treatment is available (either because no standard therapy is available for theparticular disease or because the child has relapsed and standard therapy is not helping thechild). Comparative gene expression analysis offers a readout of genetic and epigeneticchanges,whichmaybetreatablewithtargetedtherapies.Itiscomplementary/additivetoDNAmutationanalyses,whicharefarmorecommonlyusedforcancercases.The goal is to provide molecular classification in difficult cases where the molecular orhistologicalsubtypeofthetumormaynotbeclear,and,usinglargedatasets(asofNovember2018, the dataset of genomic data exceeds 11,000+ tumors expression levels) to identifytumorswith similarmolecular features. CKCC is then able to identify tumor driver pathwaysthroughoutlier analyses. Thebelief is that expression analysis, paired (where available)withmoretraditionalmutationfindings,canbeusedtoprioritizepotentialcancerdriverpathwaysthathaveahistoryofresponsivenesstocertaindrugs.TheCKCCpilotprojectrevealedoverexpressionofgenesthatcouldserveasdirectandindirectdruggable targets, after analysis of 144 cases. Based on this initial finding, the team isevaluatingtheclinicalutilityoftheiranalysisframework,byassigningpatientsintooneoffourcategoriesbasedonoverexpressionofspecificdruggablepathways.ThesepathwaysareRTK:VEGFR/PDGFR/FGFR, JAK/STAT, PI3K/AKT/mTOR, Cell Cycle and a category for others whereanother pathway is overexpressed. The goal is to demonstrate that comparative geneexpressionanalysiswillofferinformationthatisnotavailablethroughtraditionalDNAanalysisalone.ThiswillbenefitCaliforniakidssufferingfromcancers;currentestimatesarethatatleast500kidsperyearwhosufferfromcancerareoutoftreatmentoptionsfortheirdisease.WiththispilotprojectCKCCseeks togatherdataonclinicalutilityofcomparativegeneexpressionanalysis,whichthencanbeusedtooffertheanalysistoallchildrensufferingfromcancer.Thisextension isofcritical importancebecause itmeansthatchildrenwhosufferfromcancerwillbe treated with a precision medicine approach at the outset, often removing years ofunsuccessful and painful treatments, accompanied by short- and long-term side effects. Themore data that can gather now as to the clinical utility of big data comparative genomicanalysis, themore theCKCC teamcanbring this approach into a standard clinical setting, tobenefitallchildrentargetingtreatmenttotheirspecificdiseasesearlyandeffectively.Lessons learned include the need for early testing and early intervention; waiting until kidsreach the critical, out-of-treatments stage results in devastating consequences for the kids,familyandtheCaliforniahealthsystem.Manyof thechildrenreached in thispilothavegonethrough years of treatment and suffered serious effects from the treatment and thediseaseprogression. The earlier precisionmedicine analysis can enter standard treatment protocols,thegreater thechangesof recoveryandcure forchildrensuffering fromcancer.Timedelayshave devastating impacts on children’s disease progression; slowmoving systems (protocols,sequencing turn-around, drug approvals) are serious roadblocks to transforming how care is

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provided to children. Only by accepting the need for real change by advancing beyondtraditional/standard treatments and engaging with genomic analysis will practice be able toimprovethehealthoutcomesandexperiencesforchildrenwhosufferfromcancer.2.PrecisionDiagnosisofAcuteInfectiousDiseases(PDAID)PrincipalInvestigator:CharlesChiu,UniversityofCalifornia,SanFranciscoPartnerInstitutionsAbbottLaboratories,Inc.*AmericanTissueCultureCollection(ATCC)*Children’sHospitalColorado/UniversityofColoradoinDenver,CO*Children’sHospitalLosAngeles*Children’sNationalMedicalCenteratWashingtonD.C.DNAnexus,Inc.OxfordNanoporeTechnologies,Inc.*QuestDiagnostics,Inc.St.JudeChildren’sResearchHospitalinVanderbilt,TN*Syapse,Inc.UniversityofCalifornia,BerkeleyUniversityofCalifornia,DavisUniversityofCalifornia,LosAngelesUniversityofMaryland*USFoodandDrugAdministration(FDA)*ZuckerbergSanFranciscoGeneralHospitalandTraumaCenter*FundingCIAPM10/1/2015–8/31/2018$1.2millioninstatefunds$500,000 supplemental funding under “CIAPM Limited Competition for Supplemental Funds:RequestforProposalsCohenFoundationAward(Chiu,PI) 2/1/2017–2/1/2020 $1.3milliontotal“Validation of sequencing-based clinical diagnostics for Lyme disease and other tick-borneinfectionsfromblood”DoDTick-borneDiseaseResearchProgram(Chiu,PI) 10/17/2017-10/17/2020 $265,097total“Developmentofacombinedpathogen-hostgenomicassayfordiagnosisofLymediseaseandothertick-borneinfections”

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SandlerandBowesFoundations(DeRisiandChiu,PI) 9/1/2015–9/1/2018$2.4milliontotal In-kind funding for establishment of a Center for Next-Gen Precision Diagnostics(https://nextgendiagnostics.ucsf.edu)andclinicalassaydevelopmentCharlesandHelenSchwabFoundationAward(Chiu,PI) 6/1/2016-6/1/2019$1.2milliontotal“Clinicalvalidationofhosttranscriptomeassaysforinfectiousdiseasediagnosis”NIH/NIAID4R33AI120977-03(Chiu,PI) 1/1/2018–1/1/2021$900,000total“Real-timeunbiasedpathogendetectioninfebrileillnessesbynanoporesequencing”GeorgeandJudyMarcusFoundationAward(ChiuandMiller,PI) 9/1/2017–9/1/2018$400,000total“Implementingprecisiondiagnosticsofinfectiousdiseasesintheclinicalsetting”UCSFMedicalCenter(MillerandChiu,PI) 5/1/2015-present$500,000totalIn-kindfundingforclinicalvalidationofmetagenomicnext-generationsequencingtestingintheCLIA-licensedUCSFClinicalMicrobiologyLaboratoryProjectFailure to obtain a laboratory-confirmed diagnosis for many acute infectious diseases incriticallyillhospitalizedpatientsdirectlycontributestopoorpatientoutcomesandahighcostburdentothehealthcaresystem.AtUCSF,theChiugrouphaspioneeredtheuseofunbiasedmetagenomic next-generation sequencing (mNGS) for detection of all potential pathogens –viruses,bacteria, fungi,andparasites– inasingle test.Thegoalof thisproject is todevelop,validate, anddeploya clinicalmNGSassay fordiagnosisof clinical unmetneeds in infectiousdiseases:meningitis andencephalitis, sepsis, andpneumonia. Their accomplishments todateincludeclinicalimplementationofamNGSassayformeningitisandencephalitisdiagnosisfromcerebrospinalfluidanda1-year,prospectiveclinicalstudyof204patientsacross8hospitalsinCalifornia and United States demonstrating that this assay saves lives by yielding additionaldiagnosesthatarenotpossiblewithconventionaltesting.Theyarefurtherleveragingthedatabyusingmachinelearningapproachestodiagnosehumanimmuneresponsestoinfectionandantibiotic resistance, and are expanding our validation efforts to sepsis and pneumonia.Economiccostanalyseshavebeenperformedtounderstandtheclinicalindicationsforthetestandinwhatclinicalscenariosisitmostcost-effective.

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ThisprojectwillstronglyimpacthealthcareinCaliforniaasitprovidesacomprehensiveclinicaltest to identify infections that cannot otherwise be diagnosed, guiding timely treatment andleading to better health care outcomes at lower cost. An application to the FDA as a“breakthrough device” is pending; regulatory approval would make this test available topatients everywhere and provide a pathway for self-sustainable clinical reimbursement. Thisprojectwill expand in thenext 5-10 years to new indications (sepsis, pneumonia, joint/boneinfections,etc.)andnewtechnologies(nanoporesequencing,hostresponse-baseddiagnosis).TheCIAPMseedgrantdirectlyledtoadditionalgrantsfromphilanthropicfoundations(CharlesandHelenSchwabFoundation,StevenandAlexandraCohenFoundation,MarcusFoundation)and commercial interest from top biotech companies and venture capital firms, withnegotiationsongoing.Akeylessonlearnedisthatdownstreamimplementationoftranslationalresearch into clinical practice requires dedicated support, a team effort, and an urgency toadvance these technologies so that they can directly benefit patients in an accelerated timeframe.

Projectsstartedin20173.ArtificialIntelligenceforImagingofBrainEmergenciesPrincipalInvestigator:PratikMukherjee,UCSanFranciscoPartnerinstitutionsBrainTraumaFoundation(BTF)CommunityRegionalMedicalCenterinFresnoStanfordUniversityTBIEndpointsDevelopment(TED)Project*Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI)Consortium*UCBerkeleyZuckerbergSanFranciscoGeneralHospitalandTraumaCenterFundingLaunched in January2017,with$1.2million instate funds. Inkindsupport fromBTF,TRACK-TBI,andTED.ProjectEvery28seconds,anAmericansuffersacatastrophicneurologicemergency,mostcommonlystrokeortraumaticbraininjury(TBI).Neurologicemergenciesaffect15millionU.S.adultsandchildren annually at a cost of $115billion,which is 7%of totalU.S. healthcare spendingperyear. Since thebrain is susceptible to irreversible injurywithinminutes, immediatediagnosisandtreatmentareessential.Computedtomography(CT)scanningiscurrentlytheonlytypeofimagingusedworldwidetodiagnoseneurologicemergencies. Unfortunately,expertiseatthelevelofboard-certifiedradiologiststoaccuratelyinterpretthesescansisnotalwaysavailablein

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a timely fashion, especially at night, on weekends, or at rural health centers. Delayed orerroneousdiagnosiscanbeverycostlyintermsofliveslostandlong-termdisabilityincurred.In this project, the team has applied state-of-the-art artificial intelligence (AI) technology toautomatically recognize life-threatening findings on emergency head CT scans in patientssuspected of having TBI, stroke or bleeding due to ruptured brain aneurysms. This AItechnology, knownas “deep learning”, is also usedby large tech companies likeGoogle andFacebooktorecognizeobjectsinimages,suchasfacesoranimalslikecatsanddogs.Thisimagerecognition technology can be revolutionary for the rapid detection of emergencies such asbrainhemorrhageandswellingsothatphysicianscanbealertedforimmediateaction,therebypreventing medical errors from missed or delayed diagnosis. Testing for the automateddetection of acute brain hemorrhage shows accuracy equivalent to that of board-certifiedradiologists, and performance continues to improve. The team is working with industry toimplement this AI system in the “cloud” so that CT scans can be uploaded for analysis fromanywhereintheworld.TheimmediatediagnosisaidedbythistechnologyforrapidautomatedevaluationofheadCTcouldgreatlyimprovecareintheEmergencyDepartment(ED),especiallyrural areas, and even ambulances, intensive care units, and operating rooms that areincreasinglyequippedwithportableCTscanners.TreatmentsbegunearlyintheambulanceorEDholdtremendouspromiseforbetteroutcomes inneurologicemergencies, includingfewerdeaths and less disability. Reducing disability and shortening hospital stays also produceseconomicbenefits.Furthermore, until now, it has not been practical to analyze themillions of medical imagesresiding in research repositoriesworldwidebecause thenecessaryhumanexpertise is scarceandexpensive. TheseadvancedAI techniques can cheaplyandefficientlyanalyze these largeresearch imaging databases to produce quantitative information about clinically importantfindingsonthescans(“imagingbiomarkers”),whichcanthenbecombinedwithclinical,geneticandothertypesofpatientinformationforPrecisionMedicineresearch.Thiscanleadtobetterclinical trials for effective treatments for TBI, stroke and aneurysmal hemorrhage, which issorelyneededbecausealmostallsuchtrialshavefaileduptonow,inlargepartduetothelackofusefulbiomarkers.Inthenext5-10years,theteamplanstofurtherimprovethistechnologydevelopedthroughthisCIAPMDemonstrationProjectandextendittoothertypesofmedicalimaging (e.g.MRIscans)andotherclinicalapplications (e.g.cancer imaging)whererapidandautomated evaluation could prove beneficial to patient care. Further progress will rely onaccess to larger databases of patient scans, but in a way that preserves the privacy of theindividualsinvolved.Throughcheapcloud-baseddeliveryviatheInternet,thistechnologyhasgreat potential to achieve more equitable health outcomes by improving the access ofunderserved populations to high-quality evaluation of medical imaging, a vital and growingcomponentofmodernhealthcare.4.EarlyPredictionofMajorAdverseCardiovascularEventsUsingRemoteMonitoringPrincipal Investigators: Brennan Spiegel; Noel Bairey-Merz, Jennifer van Eyk; Cedars-SinaiMedicalCenter

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PartnerinstitutionsAgilentAliveCor*BeckmanCoulterDocuSignFitabaseFitbitHealthLoopNeoteryxSCIEXTasso*ThermoFisherScientificUniversityofCalifornia,LosAngelesFundingTheprojectlaunchedinJanuary2017,with$1.2millioninstatefundsandatotalof$639,090incontributions (Cedars-Sinai $200,000, Neoteryx $12,000, Cambridge Isotope Labs $19,090,Thermo Fisher Scientific $100,000, Beckman Coulter $50,000, and SCIEX $258,000). Theprojectwasawardedsupplemental fundsof$223,261under“CIAPMLimitedCompetition forSupplemental Funds: Request for Proposals” inOctober 2017with an additional $131,775 incontributions(AliveCor$53,350,SCIEX$1,445,Tasso$10,000,andCedars-Sinai$55,782).ProjectCardiovascular disease is the leading cause of death for bothmen andwomen in California.Preventionandtreatmentofheartdiseasearemosteffectivewhendisease isdetectedearly,butearlysignscanbeeasilymissedsincepeoplespendmostoftheirlifeawayfromadoctororhospital where it is challenging to monitor disease progression. If predictive markers areidentified earlier, then impending major adverse cardiac events (MACE) may be preventedthroughtreatment intensificationandefforts toenhancecompliancewith life-savingtherapy.Accurateassessmentofcardiovascular risk isessential forclinicaldecisionmaking in that thebenefits,risks,andcostsofalternativestrategiesmustbeweighedaheadofchoosingthebesttreatment for individuals. The outcome of interest for this study is MACE, which the teamdefinesasacompositeoutcomeofevents includingdeath (all cause),non-fatalMI,non-fatalstroke,orhospitalizationforheartfailure.ThegoalofthisprojectistousenovelremotemonitoringtechniquestoseeifthereareearlysignalsthatmightpredictwhocoulddevelopaMACE.MACEincludeseventslikeaheartattackorstroke.Theteamhascompletedrecruitmentofaround200Californianswithheartdiseasewhounderwentremotemonitoringforseveralmonthseach.Theremotemonitoringincludeduse of a Fitbit device tomonitor step counts, heart rate, and sleep, alongwith a specializedremoteEKGheartmonitorcalledKardia.BothofthesesensorsaremanufacturedbyCaliforniacompanies.Inaddition,wemonitoredbloodtestsusingahome-basedtestingkitdevelopedbyaCaliforniacompanycalledNeoteryx.Finally,patientsinthisstudyalsomonitoredtheirquality

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of lifeandsymptomsusinganappcalledHealthLoop,which isalsodevelopedbyaCaliforniacompany.TheyarenowanalyzingallthedatatoseeifthereareearlycluestopredictwhocouldhaveaMACE occur. They are also evaluating whether this could be a cost-effective approach tomanagingheartdisease.Becauseheartdisease is the topcauseofmortality inCaliforniaandbeyond, this study lays groundwork to evaluate more efficient, modern, and cost-effectiveapproaches to remotely monitoring and predicting early signs of MACE, hopefully with theeventualgoalofinterveningsooner.5.FullGenomeAnalysistoGuidePrecisionMedicinePrincipalInvestigator:DavidMartin,Children’sHospitalOaklandResearchInstitute(CHORI)PartnerinstitutionsGenomeOne*HumanLongevity*IlluminaUniversityofCalifornia,SanFrancisco(UCSF)UCSFBenioffChildren’sHospitalOaklandUniversityofCalifornia,BerkeleyFundingLaunched in January2017,with$1.2million in state funds.All personnel, exceptHazelPerryand Dario Boffelli, provide their time in-kind. Computational resources in excess of thesupportedlevelareprovidedin-kindatCHORI,UCSF,andUCBerkeley.ProjectThisprojectwilladvanceprecisionmedicinebydevelopingmethodstoidentifymutationsthatcause inbornor inheriteddiseases,andassemblinga teamofdoctorsandscientistswhocancarryoutthosemethods.Theteamwilleventuallybecomepartof larger internationalteams,with the long-term goal of creating a catalogue of all DNA variants that can cause humandisease.Most inheriteddiseasesbecomeapparent inchildhood;analysisofapatient’sentirecomplementofDNAcanoftenfindthedefectivegeneresponsibleforadisease.Theyusefullgenome analysis, a method developed by one member of the team, to provide a morecompletepictureofabnormalities inan individual’sDNA.Theprojecthasachieved itsgoalofsequencingthegenomesoffiftychildrenaffectedbygeneticdisorders,andtheirparents.Theyhavebeenabletoidentifygeneticvariantsresponsiblefordiseasein12the28casesanalyzedtodate.Theveryhigh identificationratedirectlybenefitspatientswhoreceiveadiagnosis,bysolvingmedical mysteries that frequently require lengthy diagnostic odysseys with uncertainoutcomes. The answers produced by full genome analysis give patients and their doctorsinsightsthatpermitappropriatemanagementoftheconditionandtherebyreducethecostsofcare. The teamenvisions thedata generatedby this project contributing to anational effort

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thatwillproducea large-scaledatabaseandenabletheeffectivecomputational identificationof genotype-phenotype associations. This will progressively expand the set of actionablegeneticvariants,allowingmorechildrentobenefit fromfullgenomeanalysis.CIAPMsupporthasallowedthemtoassembleateamanddevelopastandardizedpipelinefortheacquisitionand delivery of clinical genome sequence data, which will serve as the nucleus of a largerprogram.Thereisavastassortmentofcases,evenifonlypediatriccasesareconsidered,thatare likely tohave a genetic cause; thus, full genomeanalysis couldprove tobe verybroadlyuseful.Thisproof-of-conceptworkhasprovidedvaluablelessonsforthesuccessfulcontinuationoftheproject, and theyareworking to secure funds to continue theproject. Thework todatehasgiventheteamaclearerpictureoftheeffortrequiredforcaserecruitmentandcomputationalanalysis,andthechallengesofenlistingandsustainingtheparticipationofphysicianswhoarenotfamiliarwithgenetics.6.PersonalMobileandContextualPrecisionHealth(PERCEPT)PrincipalInvestigator:NicholasAnderson,UCDavisPartnerinstitutionsiHealthLabs*OverlapHealthUniversityCalifornia,BerkeleyUniversityofCalifornia,SanFranciscoFundingLaunchedinJanuary2017,with$1.2millioninstatefunds,iHealthcontributedin-kindsupportof$10,000inservicesanddevicediscounts.ProjectThePERCEPTprojectsoughttodevelopandevaluateanintegrativepersonalizedhealthsystemthat allows patients the ability tomanage theirmedically diagnosed chronic care conditionsunder the direction of their physicians, using their personally ownedmobile phones, and incontextoftheirownpersonalclinicaldatahistory.Thegoalofthisprojectwastoidentifyandovercome barriers for any chronic-care patient to take an active and sustained role in theirpersonal healthmanagement, and empower them in health decisionmaking through sharedprovisioning of their personal outcomes data (blood pressure, mood scales, medicationcompliance), as well as ubiquitous monitoring data from their phones. The project enrolledover 170 patients with medically diagnosed depression and hypertension to study ofengagement,communicationandbehaviorchangeon theirpersonalAndroidor iPhones.Themajorityofpatientscompletingthestudyreportedenthusiasmwithhavingtheopportunitytoshare management of their health, with many requesting additional means to sustainengagement beyond this study, such asmore dynamic goal setting capabilities, frequency ofcommunicationprompts,andenhancedapplicationusability.

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AmajorityofCaliforniacitizensareconnected-nearlycontinuously-throughsmartphonestoeachother, totheir friends,and increasinglytotheirhealthdata,yetrarelydotheyhavetheopportunitytouseself-monitoringdatacapturedthroughtheirdailyactivitiesaspartoftheirpersonalized clinical health management. As the cost of health care continues to grow forchronicdiseasemanagement, fewerpatientswill seek regular clinicalexpertise tocoordinatetheir care management for reasons ranging from scheduling, transportation, or concernsrelating to insurance. This pilot project can be an example of a new form of personalizedprecisionhealth,wherepatientsprovidetheirownexistingandnearly-ubiquitoustechnology,adoptapplicationsdevelopedthrough industrypartnershipsbasedonrecommendationsfromtheir care providers or chronic care communities, and define conditions to link theirpersonalizeddatatoclinicaldataandexpertise,wherevertheylive.7.PrecisionMedicineforEarlyProstateCancer:IntegratingBiologicalandPatientComplexityVariablestoPredictTreatmentResponsePrincipalInvestigator:SheldonGreenfield,MD(UniversityofCalifornia,IrvineandUCIMedicalCenter)PartnerinstitutionsCedars-SinaiMedicalCenterUniversityofCalifornia,LosAngelesMedicalCenterVeteransAffairsLongBeachHealthcareVeteransAffairsLosAngelesGenomeDxBiosciencesAmbryGeneticsCorporation*FundingThis study was launched in January 2017, with $1.2 million in state funds and received asupplementalawardof$246,205under“CIAPMLimitedCompetitionforSupplementalFunds:Request for Proposals” in October 2017. In-kind contributions from Health Policy ResearchInstituteandtheDonaldBrenFoundationadded$480,000insupportfromUCI.Theteamhasalso leveraged in-kind support from twoCalifornia corporations.GenomeDXBioscienceswhohas performed the Decipher genomic tests and Ambry Genetics Corporation who hasconducted the genetic tests on prostate tissue. Both companies have agreed to absorb thecostsofthetestsnotcoveredbyMedicareorinsurance.ProjectProstatecanceristhemostcommoncancerinmenandisthesecondleadingcauseofcancerdeathinmen,affectingroughlyoneinsevenmenovertheir lifetime.Patientsdiagnosedwithprostate cancer can face difficult choices about treatments thatmay involve significant sideeffects.Oftendoctorsmustcounselthemwithoutadequatedatatoexplainthelikelihoodthata given therapywill succeed. The goal of this project is to developways to predict, prior totreatment, which therapy will work best for each patient, given how far this disease hasprogressed and his tolerance for side effects. The project aims to employ a computationalapproach that considers socioeconomic, health status and other types of data, including

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traditionalseverity indicators,andagenomictestthatmeasurestheprobabilityofapatient’scancer spreading after surgery. The final combined prediction model will aid doctors andpatients in personalizing prostate cancer treatment decisions tomaximize effectiveness andminimizesideeffects,andchoosethetreatmentoptimalforindividualpatients.In 2018, it is estimated that 15,190 men will be newly diagnosed with prostate cancer inCalifornia. Disparities in the outcomes of prostate cancer treatment persist, with African-Americanmeninparticular,atgreaterriskforpooroutcomes.Atpresent,physicianshaveonlyclinical information (e.g. PSA levels, tumor stage, biopsy results) to guide treatmentrecommendations. The goals of this projectwere to provide, for allmenwith early prostatecancer,theinformationonwhichtobasetheirtreatmentdecisions.Morespecifically,thegoalswereto: (1)assessthereproducibilityoftheriskpredictionmodel indiversepopulationsandclinical settings; (2) assess the value of the addition of genomic information to the riskpredictionmodel; and (3)build adynamicupdatable registryusing the riskpredictionmodelvariablesthatcanfurtheraddtotheabilityofprovidersandpatientstopersonalizetreatmentoptionstooptimizehealthoutcomes.Boththeoutcomesofthisstudyandtheregistrythatiscreated, will provide the information needed at diagnosis to support the doctor-patientconversationsthatwillhelpthesemenchooseanoptimalpersonalizedtreatment.Thisprojectcouldserveasthebasisforanationalmodelofpersonalizedmedicineforprostatecancer.Theteamhassuccessfullyachievedandsurpassedthetargetrecruitmentgoalof600menwithnewlydiagnosedlowriskprostatecancer.Theyhavecreatedadatabaseofsurvey(e.g.stress,resilience,qualityoflife,satisfactionwithcare),medicalrecordandadministrativedataaswellas genomic data. The sample has substantial variability by patient characteristics, includingrace/ethnicity and socioeconomic status, and by characteristics of study sites. Preliminaryanalyses show differences in multiple survey-based, clinical and genomic variables byrace/ethnicity. The team added a new industry partner, Ambry Genetics, which has addedgermlinedata,includingsomeraregenevariants,tothetissue-basedgenomicinformationwehave collected in collaboration with GenomeDx. The addition of these variables, and theirpossible interactionswithsurvey-basedandclinicalmeasures,willallowfurther improvementoftheriskpredictionmodelsthatcansubsequentlybeusedtoenhanceprecisionmedicineforprostatecancer.Buildinguponthestatefunding,theteamanticipatesthattheregistrytheyhavecreated,anditsencrypteddataplatform,willcontinuetobeusedbyresearchers,providers,andultimatelyby patients to understand how best to further personalized treatment for prostate cancer.Whiletheyhavesurvey-basedoutcomesthattheywillusetoevaluatetreatmentoutcomesbyriskcategoryattheconclusionofthecurrentCIAPMfunding,discoveringwhichofthepatient-reported characteristics, clinical variables and genomic data, alone and in combination,contributetodiseaseprogressionorrecurrencewillrequirethemtofollowthecohortofmenover a longer time interval. To that end, additional funding from federal and foundationsources,inpartnershipwithindustrycolleagues,isbeingsought.

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Akeylessonlearnedwasthecriticalroleofindustrypartnersintheefforttoconductprecisionmedicine research. Combining the rapidly expanding field of genomics, with survey-based,medicalrecordandadministrativedatainanintegrateddatabaseallowedandwillallowfortheexamination of the interaction of these variables and subsequently to the occurrence,recurrence and progression of prostate cancer, particularly among different racial/ethnicgroups.EachsitehaditsownInstitutionalReviewBoardthatraiseddifferentissuesrelatedtoprotectionofhumansubjectsandthecreationofanintegrateddatabasewithpersonalhealthinformation. Addressingtheseconcernscauseddelays in thestartofdatacollection. Futuremulti-institutional studies would benefit from a consolidated process for human subject’sprotectionforthepurposeofconductingpersonalizedmedicineresearch.8.PrecisionMedicineforMultipleSclerosis:MakingItWorkPrincipal Investigators:Project inception:WalterF.Stewart,SutterHealth;Current:J.B.Jones,SutterHealthPartnerinstitutionsGenentech*JordanResearchandEducationInstituteNationalMultipleSclerosisSocietyUniversityofCalifornia,SanFranciscoFundingLaunchedinJanuary2017,with$1.2millioninstatefunds.Earlydiscoveryworkwassupportedby $100,000 from the Conrad N. Hilton Foundation, as well as funds from Sutter HealthPhilanthropy(i.e.,$75,000).Efforts to implementamobileapplicationpilotwillbesupportedwith $250,000 from Genentech. Finally, the Genentech Foundation provided $400,000 inadditional fundingtoexploretheuseofquantitative imageanalysis fordevelopingcohortsofMSpatientswithinhealthsystemthatcouldservetoinformtreatmentguidance.ProjectSutterHealthandUCSFpartneredtotakeprecisionmedicineformultiplesclerosis (MS) from“thebenchtothebedside”.MSaffectspeople intheprimeoftheir lives.Whilepatientsvarywidelyinhowtheyexperiencesymptoms,MScanhaveamajorimpactontheirabilitytowork,move,andperformotherroles.Asresearchspeedsuphowquicklymedicalknowledgegrows,it’sharderandharderfordoctorsandpatientstokeepup.SutterHealthandUCSFbuilttheneuroSHAREapplication(“app”)tocombinethelatestmedicalknowledgeanddatawithinputfrompatients,inasingleplace.Thegoalwastomakeiteasyfordoctors touse so they couldprovide thebest andmostprecise care for thosewithMS. TheneuroSHAREappsupportsdoctors’effortstokeeppacewiththelatestknowledgesotheycanprovidetailoredtreatmenttoeachpatienttheysee.Itbringsprecisionmedicinetothepatient–whether that is at a top-rankedUCmedical center or in a small rural clinic in the CentralValley.

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Theteamworkedcloselywithpatientsanddoctors to learnwhatwasneededtoprovidethemost preciseMS care alongwith the best patient experience. This inputwas integral to thedevelopmentofthefinalappthatwaslaunchedatthetest-sites.Theappcollectsandcombinesthelatestprecisionmedicinedatainrealtime,anddisplaysitduringthepatient’sappointment.Oneof themajor features is theelectronicquestionnaire. The teamstartedwithavalidbutcomplex MS survey tool. After much time and effort, the team developed it into aquestionnairethatpatientscancompletefromhome.Patients’answersflowrighttotheappsothey can be used during appointments to guide shared decisions about care and treatment.Thefinaleffort–stillongoing–istestingtheappwithdoctorsandpatientsinthreeneurologyclinics.Basic app design was made possible by philanthropic seed funding; however, the CIAPMfundingfromthestateallowedtheteamtotaketheappfromaconcepttoareality.Continuingforward,morefeaturesandMSdatasourceswillbeaddedoverthenextcoupleofyearsbasedon user feedback and requests. Additionally, the app will be implemented at more clinicsbeyondtheinitialthreepilotsites.ThechallengessolvedindesigningtheneuroSHAREapparecommon to most medical specialties. Over the next decade, the research team will seekadditional funding to expand the app beyond MS. This may include headache and othermovementdisorders.Translationalresearchinvolveslearninghowtosolveproblemsinrealworldsettings.Thiscanbeachallengewhenitinvolvesaddingnewtechnology,partners,anddatasources.Newwaystodoingthingsrequirecurrentprocessestobemodified,andthesemodificationsrequireearlyand frequent engagement with legal, privacy, and data security teams. When it came tocreatingtheapp,ITteamsneededtopartnerwithexpertoutsidevendors.Thisrequiresalevelofdocumentationthatcanbeatoddswithagiledevelopment.Theteamlearnedthatyouhaveto include the effort required to merge these approaches into your management plan. Ashealthcare systemsevolve tomeet thedemandsof their changingmarket, researchmustbereadytoadapt.

California’sNationalandInternationalImpactCalifornia continues to have a role in the national and international dialogue in precisionmedicine. Partners are presenting at academic and policy-oriented conferences nation-wideand internationallywithmultiplepublications inprocess intheacademicandpolicy literature(seeAppendix1andAppendix2).California’s role toadvanceprecisionmedicine servesasamodelforotherstatesaswellasenablesthepartnershipsneededacrosssectorsandexpertisetorealizeprecisionmedicine.ThisworkisimportantsothatCaliforniacontinuestobeagloballeaderintechnologicalinnovation,healthpromotion,andhealthcare.Several of the demonstration projects have generated intellectual property that is steadilymakingprogressintothehealthcaremarket,whileothershavehadtheirworkfeaturedinthenewsoratpopulartalks.The“ArtificialIntelligenceforImagingBrainEmergencies”projecthas

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securedalicensingagreementtodevelopacloud-basedapplicationoftheirneuralnetworkfordetecting and classifying traumatic brain injuries for worldwide deployment. Developmentssuchasthesewillcontinuetodevelopastheprojectsandpartnershipsmature.

Governor’sPrecisionMedicineAdvisoryCommitteeTheGovernorappointedasixteen-memberPrecisionMedicineAdvisoryCommitteeinOctober2017.Theprojectshavebeenanexcellentwaytodemonstrateprecisionhealthandmedicineapplicationsandyieldtangiblehealthoutcomeresults inthenear-termthroughcollaborative,multi-institutionalpartnerships. Yet, theprojects themselves, although important tohighlightpolicyconsiderations,didnotaddress the largerpolicy frameworknecessaryat thestateandfederalleveltoprovideasupportivepolicycontext.GovernorBrownconvenedthecommitteethroughOPRtomakeconcreterecommendationsonactions to improvehealth andhealth care throughprecisionmedicine. The actionswerenotlimited to state actions, but also included federal, local, public, private or private nonprofitsectors. The committee included several academic institutions, non-profits, and for-profits.Expertisespannedthespectrumfromhealthsystems,patientengagement,healthdisparities,economics,education,data,innovation,publichealth,andmuchmore.Thecommitteehostedsix meetings, including virtual and in-person as well as public meetings. In addition to theexpertiseofthecommittee,guestswereinvitedtoshareexpertiseonspecifictopics.The Governor asked the committee to consider some specific areas to guide their thinkingincludingbynotlimitedto:

• Barrierstousingbigdataandbetterdata.Howcanwemakeiteasierandmorelikelyforpatients, providers and researchers to use the most relevant data for prevention,managementandtreatmentofdiseases?

• Timelyimpactoncareandoutcomes.Howcanweunderstandandmeasurewhethera“precisionmedicine”approachtocareisbeingusedattherighttime,bytherighthealthcareprovidersandhavinganimpactonpatientoutcomes?

• Accessandeducation.Whocanaccessprecisionmedicine-basedcare?Howwillpatientsandproviderslearnaboutthis?

• Areasforbiggestimpact.Aretherecertaindiseaseswhereprecisionmedicinecanmakeanimmediateornear-termimpact?

• Futureof precisionmedicine.Howwill precisionmedicine-based carebe sustainable?Shouldpeoplebepreparedtospendmoreorlessmoneyonhealthcare?

Thecommitteereleased,PrecisionMedicine:AnActionPlanforCaliforniainDecember2018.2Thisreportprovidesrecommendationstoaddress1)DataintheContextofPrecisionMedicine;

2Availableat:http://opr.ca.gov/news/2018/12-26.html

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2) Californians as Partners in Care and Research; 3) Education andWorkforce; 4) RegulatoryChallenges;5)FinanceandCostModels;and6)OverarchingConsiderations.

NextStepsforPrecisionMedicineAs the program has grown, OPR, through many discussions with stakeholders, examinedcomponents of CIAPM thatwereworkingwell and areas that couldwork better to advanceprecision health and medicine in California given the national and international context.Subsequenttothoseconversations,theGovernorproposedanadditional$30millionforOPRinFY2018-2019 to establish a non-profit corporation named the California Institute toAdvancePrecisionHealth andMedicine. The plan for the institutewas to create a board of directorsincludingtheOPRdirector,directorsprofessionallyactiveinprecisionhealthandmedicinefromacross California, with directors appointed by the Senate Rules Committee as well as theSpeakerof theAssembly.Thisboardwouldhavehad fiduciary responsibilityandwouldhaverepresentedprecisionhealthandmedicineeffortsstatewide,beyondanyone institution.Theproposed statutory changes allowed the board to fundraise as a non-profit corporation,maintain tieswith the state (similar toVisit California), continue to support the competitive-peerrevieweddemonstrationprojectsatastatewidelevel,allowforlongerfundingcycles,andtransitiontomorepolicy implementationto furthersupportapolicyenvironmenttopositionCalifornia tocontinue its leadership role.The funding forFY2018-2019was supportedby theSenate,butultimatelydidnotpasswiththenewstructureinthebudgettocreatetheinstitute.The $30 million was passed in OPR’s budget for FY2018-19 with OPR’s current statutoryauthority. OPR, especially in light of the tremendous input and participation through thePrecisionMedicineAdvisoryCommittee,isinvestigatingthebestwaytocontinuetomovethisimportantworkforwardthatisreflectiveofthecuttingedgeworkhappeningacrossthestate–includingthemanyinstitutions–aswellaswaystocontinuetosupportandfosterthenetworkof cross-sector, cross-institution partners leading precision health and medicine efforts inCalifornia.

ConclusionScience,technologydevelopment,dataprocessing,andstoragecapacityarealladvancingatarapidpace.California,given itsuniqueecosystem ispoisedtocontinue its leadershiprole.Atthe heart of precision medicine is collaboration – across disciplines and institutions – toimprovehealthandhealthcareforallCalifornians.

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Appendix1:PresentationsfromDemonstrationProjectsin2018Theprojectpartnershavesharedtheircuttingedgeworkwithcollaboratorsacrossthenationandinternationally.Keypresentationsarelistedbelow.CaliforniaKidsCancerComparison:

• David Haussler gave a PMWC Silicon Valley 2018 talk entitled, “The Human GenomeVariationMap”(Jan.22-24,2018)

• DavidHausslergaveaplenarykeynoteattheMolecularMedTri-ConinSanFranciscoasarecipientoftheDiagnosticsWorldEarlyInnovatorAwardProgram(Mar.10-15,2018)

• DavidHausslerandOlenaMorozovaVaskepresentedat theBidenCancerCommunitySummit for the city of Santa Cruz centered around “Demystifying Cancer Research atUCSC”(Sep.21,2018)

• TedGoldsteingaveaTEDxSanFranciscotalkentitled,“Cancer:WhoLives?WhoDies?,”whichdiscussedacaserelatedtotheCKKC1project(Oct.9,2018)Linktovideo:https://www.youtube.com/watch?v=p5TLbO1wvSM

• Ted Goldstein, Olena Morozova Vaske, and Alenjandro-Sweet Cordero will all bespeakingatPMWCSiliconValley2019

PrecisionDiagnosisofAcuteInfectiousDisease• Charles Chiu presented a poster at the NASAHuman Research Program Investigators

WorkshopinTexason“NanoporeDNAsequencingforMicrobialDetectionandGenomeAssemblyontheInternationalSpaceStation”(Jan.24,2018)

• CharlesChiuwasaninvitedspeakerattheAmericanCollegeofMedicalGeneticsAnnualMeetinginCharlotte,NC(Apr.13,2018)

• CharlesChiupresentedattheSt.JudeHospitalGrandRoundsonClinicalMetagenomics(Apr.29,2018)

• CharlesChiupresentedat thePewFoundation/CDCMeetingonNewTechnologies inPublic Health giving a talk on “Clinical Metagenomic Sequencing for PathogenDetection”(May8,2018)

• CharlesChiupresentedattheIPFA/PEI25thInternationalWorkshoponSurveillanceandScreening of Blood-borne Pathogens in Athens, Greece on “Bloodborne PathogenScreeningusingMetagenomics”(May17,2018)

• CharlesChiupresentedattheBostonChildren’sHospitalGrandRounds inBoston,MA(July2018)

• CharlesChiupresentedatMetaSUBInternationalConferenceinBrazil(Aug.14,2018)• CharlesChiupresentedattheNextGenerationDxSummit inWashington,DCduringa

sessionfocusedon“AdvancesinNGSforInfectiousDiseaseDiagnostics”(Aug.22,2018)• CharlesChiupresentedattheInternationalConferenceofEmergingInfectiousDiseases

inAtlanta,GA(Aug.29,2018)• CharlesChiupresentedatCornellUniversityGrandRoundsinNewYork,NY(Sep.2018)

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• Charles Chiu presented at University of Arizona Bioengineering Grand Rounds (Sep.2018)

• CharlesChiupresentedatInfectiousDiseaseWeek(IDWeek)inSanFrancisco,CA(Oct.2-7)

• WeiGupresentedattheInternationalConferenceonClinicalMetagenomicsinGenevaSwitzerland giving a talk entitle, “Pathogen Detection Using Cell-free DNA in BodyFluids”(Oct.18,2018)

ArtificialIntelligenceforImagingBrainEmergencies

• PratikMukherjeegaveaPMWCMichigan2018talkentitled,“Precision ImagingoftheHumanBrainConnectome”(Jun.6-7,2018)

• Pratik Mukherjee presented at the Silicon Valley Big Data Science AI in HealthcareMeetup giving a talk entitled, “Artificial Intelligence inMedical Imaging” inMountainView,CA(Jun15,2018)Linktovideo:https://www.youtube.com/watch?v=ejgscF9VvJM

• Weicheng Kuo presented a poster at the 21st International Conference on MedicalImage Computing & Computer Assisted Intervention (MICCAI) in Granada, Spainentitled, “Cost-sensitive Active Learning for Intracranial Hemorrhage Detection” (Sep.18,2018)

EarlyPredictionofMajorAdverseCardiovascularEventsUsingRemoteMonitoring

• JenniferVanEykpresentedattheMassSpectrometry:ApplicationstotheClinicalLabinPalmSprings,Californiagivingatalkentitled,“DataonthecomparisonofApoB/ApoA-1ratios fromplasma and correspondingMitra tips showing a linear correlation” duringthePlenaryPanel:TheFutureofClinicalMassSpectrometry(Jan.23,2018)

• KellyMouapigaveaposterpresentationattheAmericanSocietyforMassSpectrometry2018 Meeting in San Diego, CA on “Mitra® microsampling devices in remote,longitudinal monitoring of apolipoprotein B/apolipoprotein A-I in patients at risk forcardiacevents”(Jun.6,2018)

• KellyMouapigavearesearchtalkattheHumanProteomeOrganizationWorldCongressin Orlando, Florida entitled, “Evaluating Mitra® Microsampling Devices for RemoteMonitoringofApoliproteinsinPatientsatRiskforCardiacEvents”(Oct.1,2018)

• Abstract for oral presentation was accepted for the 2019WesternMedical ResearchConference in Carmel, CA entitled, “Early Detection of Atrial Fibrillation-Atrial FlutterUsingRemotePatientMonitoring”(January2019)

PersonalMobileandContextualPrecisionHealth

• Nick Anderson presented a poster at the American Medical Informatics Association(AMIA)SummitinSanFrancisco,CAentitled,“LinkingClinicalEventstoPatientReportedmHealthData”(March13,2018)

• Meghana Gadgil presented a poster at the Society for General Internal MedicineNationalMeeting in Denver, CO entitled, “Using Patient-Reported andMobile HealthDatainPractice:FocusonHypertensionandDepression”(Apr.12,2018)

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• NickAndersonpresentedPERCEPTatUCSFfocusingonthementalhealthaspectofthestudy

• Precision Medicine for Early Prostate Cancer: Integrating Biological and PatientComplexityVariablestoPredictTreatmentResponse

• SheldonGreenfield gaveaPMWCMichigan2018 talkentitled, “Biological andPatientComplexityVariableIntegrationPredictsTreatmentResponse”(Jun.6-7,2018)

• AbhinavGroverpresentedaposterattheAmericanSocietyofHumanGeneticsAnnualMeetinginSanDiego,CAentitled,“Associationofrace,socioeconomicstatusandstresswith Decipher® genomic classifier risk scores and gene expression: Implications onprostatecancerpersonalizedtreatments.”(Oct.19,2018)

PrecisionMedicineforMultipleSclerosis:MakingItWork

• Stephen Hauser gave a presentation at American’s Committee for Treatment andResearchinMultipleSclerosisinSanDiego,CAentitled,“OcrelizumabSafetyinPatientswithMultipleSclerosis:UpdatedAnalyseswithaFocuson Infusion-RelatedReactions”(Feb.1,2018)

• Joanna Cooper, JB Jones, Joshua Liberman, andWalter Stewart led a panel at AMIA2018InformaticsSummitinSanFrancisco,CAentitled,“CanInformaticsReturntheJoyofMedicine?ARealWorldPilotinNeurology”(Mar.13,2018)

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Appendix2:PublicationsfromDemonstrationProjectsin2018Furthermore,severalprojectteamshavealreadypublishedsometheirfindingsinthescientificliterature.CaliforniaKidsCancerComparison

• Preparingamanuscripton“Barriers toDataSharing”witha focusonpediatriccancergenomicdatasets.

PrecisionDiagnosisofAcuteInfectiousDisease

• GuW,Miller S, Chiu CY. 2018. ClinicalMetagenomicNext-Generation Sequencing forPathogenDetection.AnnualReviewofPathology:MechanismsofDisease14:317-36DOI:https://doi.org/10.1146/annurev-pathmechdis-012418-012751

• Miller S, Naccache S, Samayoa E,Messacar K, et al. 2018. Laboratory Validation of aClinical Metagomic Sequencing Assay for Pathogen Detection in Cerebrospinal Fluid.BioRxiv.DOI:https://doi.org/10.1101/330381

• Additionalmanuscriptsare inpreparation fornewadvancements in themetagenomicnext-generation sequencing (mNGS) pipeline and cost-benefit analysis of mNGSpathogendetectioncomparedtoconventionaltesting

ArtificialIntelligenceforImagingBrainEmergencies

• Kuo W, Häne C, Yuh E, Mukherjee P, Malik J. 2018. PatchFCN for IntracranialHemorrhageDetection.ArXiv.https://arxiv.org/abs/1806.03265

• KuoW,HäneC, YuhE,MukherjeeP,Malik J. 2018.Cost-SensitiveActive Learning forIntracranialHemorrhageDetection.ArXiv.https://arxiv.org/abs/1809.02882

• Anadditionalmanuscript related to theperformanceof theneural networkhasbeensubmittedforpublication.

EarlyPredictionofMajorAdverseCardiovascularEventsUsingRemoteMonitoring

• SpeierW,DzuburE,ZideM,ShufeltC.,etal.2018.Evaluatingutilityandcomplianceinapatient-based eHealth study using continuous-time heart rate and activity trackers.JournaloftheAmericanMedicalInformaticsAssociation25(10):1386-91

• Threemoremanuscriptshavebeeneithersubmittedorareacceptedbutnotavailableonlineyet.