learning and mapping lyme disease patient trajectories ... · 12/23/2017 · comorbidities and...

LearningandMappingLymeDiseasePatientTrajectoriesfromElectronicMedicalDataforStratificationofDiseaseRiskandTherapeuticResponse

OsamuIchikawa1,2*,BenjaminS.Glicksberg1,3*,BrianKidd1,LiLi1#,JoelT.Dudley1#

1. DepartmentofGeneticsandGenomicSciences,InstituteforNextGenerationHealthcare,IcahnSchoolofMedicineatMountSinai,770LexingtonAve.,NewYork,NY10065.

2. DrugResearchDivision,SumitomoDainipponPharma.Co.Ltd.,3-1-98Kasugade-naka,Konohana-ku,Osaka,554-0022,Japan.

3. InstituteforComputationalHealthSciences,UniversityofCalifornia,55016thSt,SanFrancisco,California,94158.

*Theseauthorscontributedequallytothiswork

#Correspondenceandrequestsformaterialsshouldbeaddressto

Dr.LiLi([email protected])orDr.JoelDudley([email protected])

InstituteforNextGenerationHealthcare

IcahnSchoolofMedicineatMountSinai

770LexingtonAve.

15thFloor

NewYork,NY10065,USA

.CC-BY-NC-ND 4.0 International licensenot certified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprint (which wasthis version posted December 23, 2017. . https://doi.org/10.1101/239020doi: bioRxiv preprint

https://doi.org/10.1101/239020

http://creativecommons.org/licenses/by-nc-nd/4.0/

2

ABSTRACT(250words)

Background

Lymedisease(LD)isanepidemic,tick-borneillnesswithapproximately329,000incidencesdiagnosedeachyearinUnitedStates.Long-termuseofantibioticsisassociatedwithseriouscomplications,includingpost-treatmentLymediseasesyndrome(PTLDS).ThelandscapeofcomorbiditiesandhealthtrajectoriesassociatedwithLDandassociatedtreatmentsisnotfullyunderstood.Consequently,thereisanurgentneedtoimproveclinicalmanagementofLDbasedonamorepreciseunderstandingofdiseaseandpatientstratification.

Methods

Weusedaprecisionmedicinemachine-learningapproachbasedonhigh-dimensionalelectronicmedicalrecords(EMRs)tocharacterizetheheterogeneouscomorbiditiesinaLDpopulationanddevelopsystematicpredictivemodelsforidentifyingmedicationsthatinfluencetheriskofsubsequentcomorbidities.

Findings

Weidentified3,16,and17comorbiditiesatbroaddiseasecategoriesassociatedwithLDwithin2,5,and10yearsofdiagnosis,respectively.AthigherresolutionofICD-9levels,wepinpointedspecificco-morbiddiseasesonatimescalethatmatchedthesymptomsassociatedwithPTLDS.Weidentified7,30,and35medicationsthatinfluencedtherisksofthereportedcomorbiditieswithin2,5,and10years,respectively.Thesemedicationsincludedsixpreviouslyassociatedwiththeidentifiedcomorbiditiesand29newfindings.Forinstance,thefirst-lineantibioticdoxycyclineexhibitedaconsistentlyprotectiveeffectfortypicalsymptomsofLD,including‘backacheNotOtherwiseSpecified(NOS)’and‘chronicrhinitis’,butconsistentlyincreasedtheriskof‘cataractNOS’,‘tearfilminsufficiencyNOS’,and‘nocturia’.

Interpretation

OurapproachandfindingssuggestnewhypothesesforprecisionmedicinetreatmentsregimensanddrugrepurposingopportunitiestailoredtothephenotypicprofilesofLDpatients.

Funding

TheSteven&AlexandraCohenFoundation


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INTRODUCTION Lymedisease(LD)isavector-borne,infectiousdiseasecausedbythebacteriumBorreliaburgdorferithatistransmittedtohumansthroughtickbites.AccordingtotheUSCentersforDiseaseControlandPrevention(CDC),around329,000LDcasesoccurannuallyanditbecomesamajorUSpublichealthproblemthatcausessubstantialuseofhealthcareresources.LDismostprevalentintheNortheastandupperMidwest,and95%ofallconfirmedcasesin2015werereportedin14states1.ThesymptomologyofLDisheterogeneous,althoughsomegeneralpatternshaveemerged.ThefirstmanifestationofLDisoftenanexpandingannularlesion,callederythemamigrans,nearthebitelocation,butthissignispresentinonly70–80%ofpatients2.Thelengthoftimefortherashtooccur,alongwiththecharacteristicsoftherash(e.g.,compositionandsize)canalsovary3.Otherclinicalfeaturesthatoftenarise,singlyorincombination,includefever,pain,arthritis,myopericarditis,neurologicalsymptoms(e.g.,facialnervepalsy),andsatelliterashes.Oneexplanationforthisvariabilityisthatthegenotypeofthetickitselfmightaffectaspectsofpathogenesis,suchastheprobabilityofhematogenousdissemination4,5.TheneurologicalmanifestationsinLD,reportedin3–12%ofpatients,areofgreatestconcern6.Thesephenomena,collectivelycalledneuroborreliosis,areoftenassociatedwithintensepainthatcanmanifesteithersoonafterinfectionormuchlater,frommonthstoyearsafterward. AccurateandprecisediagnosesofLDpresentseveralchallenges.Typically,laboratorytestingofLDfollowsidentificationofcutaneousmanifestationsfromvisualinspectionbutthesemanifestationsarenotalwayspresent.Currentguidelinesrecommendserologictesting,atwo-phaseprocessconsistingofanenzymeimmunoassaywithin30daysofsymptomonset,followedbyWesternblotafter30daysfromsymptomoccurs7,8iftheearlytestisactive.Eventogether,thisdiagnosticstrategyhaspoorsensitivity,particularlyduringtheacutephase,withfalse-negativeratesofupto50%9.Otherlaboratorymethodsarespecificforparticularmanifestations,e.g.,testingofCSFforcentralnervoussysteminvolvement.RecentworkhasshownthatincorporationofdatafromvariouswearabledevicescandetectearlysignsofLDandassociatedinflammatoryresponses.Forexample,variationsinperipheralcapillaryoxygensaturation(SpO2),amarkerassociatedwithphysiologicalmacro-phenotypessuchasfatigue,canbemeasuredbyportablebiosensorstofacilitatemoreaccurateandrapidLDdiagnosisfromvariationsinthesemeasurementsandcouldbeeconomicallyfeasibleforwidespreaduseinthefuture.Currently,however,cliniciansstillhavetorelyontraditionalmeasurestodiagnosepatients10.Furthermore,comorbidconditionscaninterferewithbothdiagnosisandtreatment.Forinstance,otherinfectionscanbeconcurrentlytransmittedwithLD11,makingdifferentialdiagnosisevenmoredifficultandsometimesrequiringspecialized,alternativetreatmentstrategies.ManystudieshaveattemptedtodevelopmethodsfordifferentiatingLDfromothersimilarsyndromes,e.g.,septicarthritisvs.LDofthekneeinchildren12. Followingsuccessfuldiagnosis,LDismostcommonlytreatedwithantibioticssuchasdoxycycline,amoxicillin,cefuroximeaxetil,andceftriaxone.Althoughthesemedicationshave


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highcurerates(~90%)13,theyareassociatedwithseriouscomplicationsandadverseevents,especiallyunderprolongeduse14,153,16.Notablyinthisregard,onestudyshowedthatcertainfirst-linetreatments,specificallyintravenousceftriaxonefollowedbydoxycyclineforchronicLDpatientswerenoteffectivecomparedtoplaceboforcingdiscontinuationofthetrial17.AnotherstudyreportedthatrepeatedIVceftriaxonetreatmentforLymeencephalopathyresultedinonlyminorcognitiveimprovements,withhighratesofrelapseofcognitivesymptoms18.ThesefindingssuggestthatunknownfactorsareresponsibleforthehighvariabilityoftreatmentoutcomesforpatientswithLD.Additionally,upto20%oftreatedpatientsdeveloppost-treatmentLymediseasesyndrome(PTLDS),inwhichlingeringsymptomssuchasfatigue,pain,orjointandmuscleacheslastformonthsorevenyears.Thecausesandfrequenciesofthesesymptomsremainunclear,andtheissueisfurtherconfoundedbythepresenceofconcurrentdiseases. SeveralrecentstudiesrevealtheuncharacterizedcomplexityofdiseasecourseandtreatmentresponseinLD.Onestudyfoundcertainfirst-linetreatments,specificallyintravenousceftriaxonefollowedbydoxyclycline,forchronicLDpatientswerenoteffectivecomparedtoplaceboandwereforcedtodiscontinuetheirstudy17.AnotherstudyassessedtheeffectsofrepeatedIVceftriaxonetreatmentforLymeencephalopathyandfoundonlyminorcognitiveimprovementswithhighratesofrelapseincognitionissues18.Therefore,itseemsthatthereareotherfactorsatplaythatmayexplainthehighvariabilityoftreatmentoutcomesforpatientswithLD.Itisdifficulttodisentangletowhatextentgiventreatmentresponsesanddiseasesequelaeareduetodifferencesinindividualimmuneresponses,patientcharacteristics,diseaseburden,andtreatmenttiming,ortothemedicationsthemselves.Indeed,itisverylikelythatresponseandoutcomedependonacomplexinterplaybetweenthesefactors,makingclinicians'jobsextremelydifficult.Toaddressthediversesymptomology,imperfectdiagnosticstrategies,andvariabletreatmentoutcomesofLD,comprehensivestudydesignsarerequired.Forexample,aninvestigationofriskfactorsforLDinfection,suchasbehavioralandenvironmentalriskfactors,revealedthatLD–positiveserologyissignificantlyassociatedwithclinicalanddemographicfeaturessuchaspreviousself-reportedLDdiagnosisandage,behavioralfactorssuchaswearingprotectiveclothing,andgeographic/environmentalfactorssuchasshrubedgedensityinpropertylocation19.Anotherstudyevaluatedtheriskstoindividualsbasedongeographicalfeaturessuchasthesuitabilityofthelocalhabitatforticks20. Althoughtheaforementionedstudieshaveprovidedagreatdealofusefulinformation,thevariabilityinglobalriskprofilesforLDpathogenesisremainsincompletelyunderstood,andthereisanunmetneedforpersonalizedtreatmentrecommendationsthattakeintoaccountindividualcharacteristicssuchasdemographicsanddiseaseburden.ElectronicMedicalRecords(EMRs)fromhospitalscontainawealthoflongitudinal,patient-leveldataencompassingpriorhistoryofprescriptionsanddiseasediagnoses,alongwithclinicaloutcomes,thatcanbeexploitedtoinvestigatetheseissuesinadata-drivenfashion.TodatetherehasbeennosystematicanalysisofLDusingEMRdata,particularlyfromahospitalwithinahigh-riskstate.In


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thisstudy,weleverageanEMRdatasetrepresentingoverfivemillionuniquepatientsofdiverseracialandethnicbackgroundscollectedfromalargeacademicmedicalcenterinNewYorkCity.Althoughnotitselflocatedadjacenttoawoodedarea,MSHcaterstopatientsfromalloverthestate.NewYorkisoneoftheaforementioned14statesreportingthevastmajorityofLDcases,andin2017hadanincidencerateof16.4per100,000individuals(CDC),oneofthehighestinthecountry. WehypothesizedthatEMRdatafromMSHcouldprovidearichframeworkforstudyingtheheterogeneityofLymemanifestation,aswellasthequalityandefficacyoftreatment.Usingvariousstate-of-the-artstatisticalandmachinelearningmethods,wesoughttoidentifypatternsofclinicaloutcomesinordertohelpphysiciansdeveloptreatmentstrategiestailoredtopatients'diseaseprofiles.Specifically,weinvestigatedhowdemographicandclinicalfactorsaffectLDmanifestationsandclinicaloutcomesinthecontextofvarioustreatments.OurmaingoalsweretoidentifycomorbiditiesassociatedwithLDanddevelopasystematicpredictivemodelforidentifyingmedicationsthatinfluencetheriskoftheseconditions.Asanalternativetoone-size-fits-allstrategiesfortreatingLD,ourmethodologyfacilitatesdirectingtreatmentrecommendationsandidentifyingpossiblerepurposingopportunitiestailoredtothephenotypicprofilesofLymepatients.Ourstudyisthefirstdata-drivenefforttoprioritizemedicationsforLDbasedonanindividual’sphenotypeprofile.WeidentifiedLyme-associatedcomorbiditiesatthelevelofbroaddiseasecategories,pinpointedspecificco-morbiddiseasesassociatedwithLDovertime,andusedmachinelearningtopredictmedicationsthatinfluencetherisksofthesecomorbidities. WeexpectthatthenovelframeworkandfindingsfromthisstudycansupportcurrentandfutureeffortstodeveloppersonalizedtreatmentstrategiesforpatientswithLD,includingeffortstoprovidephysicianswithabroaderevidentiaryfoundationonwhichtobasetheirtreatmentrecommendations(e.g.,selectionofantibiotics)basedonindividualpatients'diseaseriskprofiles.Additionally,morepreciseknowledgeofpredictedadverseeventswouldfacilitateimprovementsinmonitoringandmanagementstrategies.


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METHODSPatientpopulationandstandardizationofclinicalterminologyPatientcohortWeutilizedElectronicMedicalRecords(EMRs)fromtheMountSinaiDataWarehouse(MSDW),thelargestcomprehensiveEMRsysteminNewYorkCity,whichincludesdatafromaraciallyandethnicallydiversepatientbase.Since2000,morethan4.5millionuniquepatientrecordshavebeendocumentedinthissystem.DiseasediagnosesareencodedasInternationalClassificationofDiseases,9thRevision(ICD-9)billingcodes,whichhavebeenusedextensivelyinEMR-relatedanalyses21.Inthisstudy,weretrievedrecordsfromallpatientsdiagnosedwithLymedisease(LD)withtheICD-9code088.81(n=2,134).Werestrictedthedatatorecordsoccurringbetween2000and2015,allowingforupto15-yearfollow-up.InaccordancewithHealthInsurancePortabilityandAccountability(HIPAA)andProtectedHealthInformation(PHI)guidelines,theagesofthesepatientswerecensoredat18and90.Finally,weonlykeptdatafrompatientswithdefinedage,self-reportedsex,andself-reportedrace/ethnicity(referredtoas“race”inthismanuscript).Forthetotalof1,767Lymepatients,therewere930females(52.6%)and837males(47.4%),withanaverageageof47.8±19.7.Theracialbreakdownofthecohortisasfollows:1,201Caucasian(70.0%),49African-American(2.8%),34Hispanic/Latino(1.9%),and483Others(27.3%).Forthesepatients,wealsoretrievedallotheravailableclinicalvariablesfromEMR,includingprescriptionsandotherdiseasediagnoses.Inaddition,weretrievedIgM/IgGlabmeasurementspertinenttoLD.IgMorIgGWesternblotlabswereavailablefor28patientsafteroratthetimeofdiagnosis(45dayswindowofdiagnosis).Ofthose,89%patients(25/28)werereportedaseitherIgMorIgGWesternblot–positive,confirmingtruepositivityforLyme.Theremaining11%ofpatients(3/28)werereportedasIgM-negative,butallwerepositiveforp23,anantigenspecifictoLyme.Intotal,wecompiled3,936diseasesdiagnosisand5,723prescriptions.Weprovideaschematicofourstudydesign,approach,andpatientselectioncriteriainFigure1.ClinicalsourcesandtermstandardizationWecategorizeddiseasesusingtheClinicalClassificationsSoftware(CCS)forICD-9diagnosiscodes,developedbyAHRQ22,whichaggregatesandcharacterizesmorethan14,000ICD-9codesintobroadercoherentdiseasecategories.ThisstrategyhelpstoavoidsamplesizelimitationasaresultofusingICD-9codesalone.Forcategorization,weusedthe‘Single-LevelDiagnosis’(CCS-single)level,whichhasatotalof283differentcategories.WestandardizedmedicationdatabymappingtotheRxNormontology23.Specifically,wemappedthesetermstoingredientcodes,yielding793normalizedmedications.Toensuretherobustnessofouranalyses,werequiredasamplesizeof>20patientsforcalculationsofthesignificanceofdiseasedirectionalityanddisease–medicationassociation.


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MachinelearningmethodsandanalysisDiseasepairtemporaldirectionalityForallpatientswithLD,wefirstassesseddisease-pairconnectivitypatternsforcomorbiddiseases.Specifically,wedeterminedwhetherthemembersofeachpairexhibitedasignificantpatternintheirtemporalorder,e.g.,whetheroneprecededtheothermoreoftenthanexpectedbychance.WeperformedacumulativebinomialprobabilitytesttoassessthetemporalorderingoftheassociationsbetweenLymeandallotherdiseases,assuminga50%probabilityofeithertooccurbeforetheother.Weperformedthefollowinganalysisonbothbroadandnarrowdiseasecategories.Atthebroaderlevel,weanalyzedrepresentativeCCS-single-levelcategoriesbecausethisstrategycouldenhancesignalsthatmightbelostduetosmallsamplesizeattheICD-9level.Second,weperformedtheanalysisusingstandardICD-9codesinordertodetectassociationsatahigherresolutionforcertaincodesthatmaybemoreprevalent.Becausethesecomorbidconditionscanbeeitherchronicoracute,weperformedseveraliterationsofthisanalysisoverdifferenttimewindows,specifically2,5,and10years.Foreachtimewindow,werestrictedcollectionofinformationforthecomorbiddiseasesinbothtemporaldirections,relativetothedateoffirstLymediagnosis.Forthe2-yearwindow,forexample,weonlycollecteddiseasedataforeachpatient2yearsbeforeand2yearsafterthedateofLymediagnosis.FortheCCS-single-andICD-9–levelanalyses,weperformed275and3,639testsforeachwindow,respectively.Last,todeterminewhetherdiseasepairswithsignificanttemporaldirectionalitywerealsosignificantlycomorbid,weperformedalogisticregressionforeachpaircontrollingforage,sex,andself-reportedrace.Theoutcomevariableinthismodelwasthediseasethatwasshowntooccuraftertheotherinthetemporalanalysis(significantinthebinomialassessment).Definitionofoutcomesandcovariatesinthemachine-learningmodelTodiscoverriskfactorsornewtherapeuticoptionsforLDsequelae,wefocusedonthenewonsetofdiseasecomorbiditiesmorethan7daysafterthediagnosisofLD.Ofthe1,767LDpatientsintheoverallcohort,wesystematicallyassessedthecomorbiditiesandmedicationassociationsfor1,196patientswhowerefollowedupformorethan7daysandhadatleastoneprescriptionrecordinMSH’sEMRsystem.Likeourdisease-pairtemporaldirectionalityanalysis,wesettimewindowsof2,5,and10years.Foreachpatient,wecollectedthediseasesdiagnosedwithin2,5,or10yearsaftertheirfirstLymediagnosisdate.Wealsoretrievedmedicationsprescribedwithin1yearpriortoand2,5,or10yearsafterthefirstLymediagnosis.OutcomecomorbiditiesweredefinedbyICD-9codeandcategorizedusingCCS-single-levelDiagnosisterms.Featureselection


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Weconsideredmanydiseasevariables,codedbyCCS-single-levelcategories,andmedicationvariables,whichweremappedtoRxNormingredientcodes.Accordingly,weadoptedafeatureselectionmethod,penalizedlogisticregressionwiththeadaptiveLASSO(Eq.1),toidentifyvariablesofthehighestrelevancethatassociatedwithensuingcomorbiditiesfollowingLDdiagnosis.TheadaptiveLASSOisanextensionofthetraditionalLASSO24thatusescoefficient-specificweights25.TheadaptiveLASSOestimatorselectsthezerocoefficientsofthetrueparametersareestimatedaszerowithprobabilitytendingtoone,whichiscalledsparsityproperty.Andthenon-zerocomponentsareestimatedasifthetruesparsemodelwereknownaprior,whichisasymptoticallynormal26.Letℒ!(𝛽;𝑌,𝑋)bethenegativelog-likelihoodparametrizedbyβforasampleofsizen.TheadaptiveLASSOestimatorisdefinedas:𝛽 = 𝑎𝑟𝑔𝑚𝑖𝑛! {ℒ! 𝛽;𝑌,𝑋 + 𝜆! 𝜔! 𝛽!!

!!! } (1)where𝜔! = |𝛽!|!!isacoefficientspecificweightsvector,and𝜆!isaregularizationparameter.Wesetthepositiveconstantγas1accordingtoZouetal.25,andobtained𝛽bythemaximumlikelihoodestimateofRidgeregression.The𝜆!valueforminimumAUCwaschosenby10-foldcrossvalidation.WeusedtheRpackageglmnet27forthesepenalizedregressions.LogisticregressionmodelWeusedoddsratio(OR)fromlogisticregression(Eq.2)toassesstheriskoffuturecomorbidityprogressiononeachmedicationtaken(i.e.eitherincreasedriskorprotectiveeffect).WeanalyzedthepairsofoutcomediseasecomorbidityandthemedicationsthatwereselectedbytheadaptiveLASSO.Inthismodel,weadjustedforage,sex,self-reportedrace,andthefollow-uptimeframe.

𝑙𝑜𝑔 !!!!

= 𝛽! + 𝛽!𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 + 𝛽!𝑎𝑔𝑒 + 𝛽!𝑔𝑒𝑛𝑑𝑒𝑟 + 𝛽!𝑟𝑎𝑐𝑒 + 𝛽!𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑟𝑒𝑑 𝑝𝑒𝑟𝑖𝑜𝑑(2)

wherePistheprobabilityofadisease,medicationisabinaryvariable,ageisacontinuousparameter, genderisabinaryvariable(Female/Male);raceisacategoricalvariable(Caucasian,AfricanAmerican,Hispanic/Latino,orOther),andobservedperiodisacontinuousparameter.𝛽coefficientsforeachcovariaterepresenttheeffectsizewhencontrollingforallothers.PropensityscorematchingTocontrolforpotentialconfoundingfactorsduetoimbalancesofclinicalcharacteristics,notlimitedtoageandgender,weanalyzedthetemporaleffectsofmedicationsafterthepropensityscorematchingtoselectanappropriatecontrolcohortforthetargetedcasecohort28.Thus,wecreatedcomparablecohorts,consistingofgroupstreatedoruntreatedwitha


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targetedmedication,basedonasetofcovariatesatthebaselinetimepoint,i.e.,timezeroforeachpatient.Thebaselinetimepointwasdefinedasthefirstprescriptiondayofthetargetedmedicationor7daysafterLDdiagnosis,whicheverwaslater,becauseweobserveddiseasecomorbiditiesformorethan7daysafterLDdiagnosis.Thepropensityscoresoftargetedprescriptionswerepredictedbyalogisticregressionmodel,includingothersignificantmedicationsanddiseaseconfoundersselectedbytheadaptiveLASSOwitha10-yeartimewindow,withpatientdemographicsascovariates.Eachpatientprescribedagivenmedicationwasmatchedtoacorrespondingcomparisonpatient(1:1ratio)bynearest-neighbormatching.Forinstance,weanalyzedassociationbetweendoxycyclineand‘backacheNotOtherwiseSpecified(NOS)'(ICD-9code:724.5),‘chronicrhinitis'(472.0),‘tearfilminsufficiency(insuffic)NOS(375.15)’,and‘cataractNOS(366.9)’,andbetweenamoxicillinand‘acuteupperrespiratoryinfection(URI)NOS(465.9)’.Atotalof328,330,358,370,and115subjectswereselectedforeachmedication-comorbiditypairinthepropensityscore-matchedtreated/untreatedgroup.TheRpackageMatchIt29wasusedforpropensityscorematching.SurvivalanalysisWegeneratedsurvivalcurvesbytheKaplan–Meiermethodandexamineddifferencesinsurvivalamongsubgroupsbythelog-ranktest,withpropensityscorematchingofcasesandcontrols.WecalculatedhazardratiosusingCoxproportionalhazardsmodels:ℎ 𝑡 = ℎ! 𝑡 exp (𝛽!𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛)(3)whereℎ 𝑡 istheexpectedhazardattimet,ℎ! 𝑡 isthebaselinehazard,andmedicationisabinaryvariable.WeverifiedtheproportionalhazardsassumptionbyconfirmingthatSchoenfeldresidualsareindependentoftime(Schoenfeldtestp>0.1).WeusedtheRpackagessurvivalandsurvminerforthesurvivalanalysis.RoleofthefundingsourceThefunderofthestudyhadnoroleinstudydesign,datacollection,dataanalysis,datainterpretation,orwritingofthemanuscript.Thecorrespondingauthorshadfullaccesstoallthedatainthisstudyandhadfinalresponsibilityforthedecisiontosubmitforpublication.


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RESULTSIdentifiedcomorbiditiesassociatedwithLymedisease,groupedasbroaderdiseasecategoriesWeassessedthetemporalorderingoftheassociationsbetweenLymedisease(LD)andotherdiseases;specifically,wesoughttodeterminewhetheragivencomorbiditytendedtooccurbeforeorafterdiagnosisofLD.Werestrictedouranalysistodiseaseswithreporteddatesandonlyincludedthefirstreportedencounterofadiagnosis,resultingin41,713disease-diseasepairs,andanalyzedtheirtemporalorderingatthepatientlevel.Specifically,foreachcomorbiddiseasepair(i.e.LDandanotherdiseasecategory),wetabulatedthenumberofpatientswithbothdiseasesandassessedwhichdiseaseinthepairoccurredfirst,oriftheyoccurredatthesametime,basedonthevisitdates.Overall,outofthe275Lyme-comorbiditycombinationsforalltimewindows,21werenominallysignificant,with5diseasesoccurringpriortoLDand16occurringafter(p<0.1;Table1a).Forthe2-yearwindow,weidentifiedthreediseasecategoriessignificantlyassociatedwithLD,withtwopriorandoneafter;forthe5-yearwindow,16categories,withfourpriorand12after;andforthe10-yearwindow,17categorieswithfivepriorand12after(Table1a).WereconfirmedsomepreviouslyreportedLymecomorbidities,including‘nutritionaldeficiencies’[p=0.069,probability(prob)=0.54at5years;p=0.035,prob=0.55at10years]30,31,‘visiondefect’(p=0.099,prob=0.57at5years;p=0.076,prob=0.57at10years)32 33,and‘disorderoflipidmetabolism’(p=0.036,prob=0.54at5years;p=0.076,prob=0.57at10years) 34.Additionally,weidentifiedseveraldiseasecomorbiditiesnotpreviouslyreported,including‘cataract’(p=0.0037,prob=0.65at5years;p=0.033,prob=0.64at10years),‘acutebronchitis’(p=0.094,prob=0.62at2years;p=0.022,prob=0.64at5years;p=0.034,prob=0.63at10years),and‘nonmalignantbreastconditions’(p=0.057,prob=0.58at5years;p=0.066,prob=0.58at10years).AcompletelistofdiseasecategoriesisshowninTable1a.


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Time

(year) Direction Disease(CCS)

Lyme

First

Disease

First

Same

Time Pvalue Prob.

2 - Coronaryatherosclerosisandotherheartdisease 18 58 17 1.10E-02 0.62

2 - Administrative/socialadmission 41 66 9 8.17E-02 0.57

2 + Acutebronchitis 23 11 3 9.39E-02 0.62

5 - HIVinfection 2 21 9 5.51E-02 0.66



5 - Disordersoflipidmetabolism 117 269 111 3.63E-02 0.54

5 + Openwoundsofextremities 24 6 0 7.15E-04 0.8

5 + Openwoundsofhead;neck;andtrunk 19 9 0 4.36E-02 0.68

5 + Fractureoflowerlimb 16 8 0 7.58E-02 0.67

5 + Cataract 57 21 10 3.67E-03 0.65

5 + Fractureofupperlimb 18 9 1 9.25E-02 0.64


5 + Analandrectalconditions 26 11 5 8.21E-02 0.62

5 + Nonmalignantbreastconditions 60 36 7 5.72E-02 0.58

5 + Othereyedisorders 75 41 14 4.76E-02 0.58

5 + Neoplasmsofunspecifiednatureoruncertainbehavior 60 39 6 8.58E-02 0.57

5 + Blindnessandvisiondefects 58 33 11 9.89E-02 0.57

5 + Nutritionaldeficiencies 219 141 47 6.85E-02 0.54

10 - HIVinfection 2 25 9 1.44E-02 0.69



10 - Disordersoflipidmetabolism 121 301 111 1.59E-03 0.56

10 - Essentialhypertension 96 271 124 1.20E-02 0.55

10 + Openwoundsofextremities 28 7 0 2.54E-04 0.8

10 + Maintenancechemotherapy;radiotherapy 14 5 1 5.77E-02 0.7

10 + Cataract 64 26 10 3.32E-03 0.64

10 + Occlusionorstenosisofprecerebralarteries 22 10 3 8.77E-02 0.63


10 + Poisoningbyothermedicationsanddrugs 24 7 8 9.98E-02 0.62

10 + Analandrectalconditions 29 14 5 9.67E-02 0.6

10 + Othereyedisorders 87 43 14 7.69E-03 0.6

10 + Nonmalignantbreastconditions 65 41 7 6.60E-02 0.58

10 + Blindnessandvisiondefects 63 36 11 7.62E-02 0.57

10 +

Inflammation;infectionofeye(exceptthatcausedbytuberculosis

orsexuallytransmitteddisease) 78 39 20 6.19E-02 0.57

10 + Nutritionaldeficiencies 228 143 47 3.51E-02 0.55


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Time

(year)

Direction

Disease(CCS)

ICD9

Disease(IC

D9)

Lyme

First

Disease

First

Same

Time

pvalue

(binom

ial)

Prob

.(binom

ial)

pvalue

(logistic

regressio

n)

OR(lo

gistic

regressio

n)

5-

HIVinfection

V08

HIVpo

sitiveNOS

021

8

1.21

E-02

0.72

1.80

E-05

2.17

5-

Administrativ

e/social

admiss

ion

V20.2

Routinchildhealth

exam

16

49

43.18

E-04

0.71

1.31

E-02

2.08

5

+Nutritiona

ldeficiencies

268.9

VitaminDdeficiencyNOS

203

124

36

1.37

E-02

0.56

1.20

E-17

75.64

5

+Ca

taract

366.9

CataractNOS

40

18

74.08

E-02

0.62

2.90

E-30

4.27

5

+Ac

utebron

chitis

466.0

Acutebron

chitis

36

16

31.50

E-02

0.65

4.02

E-21

3.56

5+

Non

maligna

ntbreast

cond

ition

s79

3.80

Unspe

cifie

dab

norm

al

mam

mog

ram

28

12

08.29

E-03

0.70

8.92

E-10

2.61

10

-

HIVinfection

V08

HIVpo

sitiveNOS

024

8

3.50

E-03

0.75

1.80

E-05

2.17

10

-Disorderso

flipid

metab

olism

27

2.0

Purehypercholesterolem

84

159

50

8.04

E-02

0.54

1.60

E-30

2.22

10

-Disorderso

flipid

metab

olism

27

2.4

Hype

rlipide

miaNEC

/NOS

97

187

64

9.01

E-02

0.54

1.06

E-18

1.78

10

-

Essentialhypertension

401.9

Hype

rten

sionNOS

96

247

120

8.16

E-02

0.53

9.83

E-08

1.39

10

-Ad

ministrativ

e/social

admiss

ion

V20.2

Routinchildhealth

exam

17

54

48.82

E-05

0.72

1.31

E-02

2.08

10

+

Nutritiona

ldeficiencies

268.9

VitaminDdeficiencyNOS

211

124

36

4.67

E-03

0.57

1.20

E-17

75.64

10

+

Cataract

366.16

Senilenuclearcataract

17

21

1.29

E-03

0.85

2.94

E-03

1.97

10

+

Cataract

366.9

CataractNOS

45

21

73.02

E-02

0.62

2.90

E-30

4.27

10

+

Infla

mmation;infectionof

eye(excep

ttha

tcau

sedby

tube

rculosisorse

xually

tran

smitted

disease)

373.00

Blep

haritisNOS

33

21

1.14

E-07

0.92

2.27

E-14

3.79

10

+

Othereyediso

rders

375.15

Tearfilm

insufficNOS

24

11

13.26

E-02

0.67

4.44

E-12

3.36

10

+

Acutebron

chitis

466.0

Acutebron

chitis

37

17

31.66

E-02

0.65

4.02

E-21

3.56

10

+Non

maligna

ntbreast

cond

ition

s79

3.80

Unspe

cifie

dab

norm

al

mam

mog

ram

31

12

02.70

E-03

0.72

8.92

E-10

2.61

Table1(a;top

)Dise

asesassociatedwith

Lym

e,analyzedasCCS-single-levelcategories(pvalue<0.1).A

totalof2

75dise

ases

weretested

.(b;bottom)D

iseasesassociatedwith

Lym

e,byICD-9category.A

totalof3

,639

dise

asesweretested

.Thistab

le

includ

esonlytheICD-9diseasesth

atareclassified

intoth

eCC

S-sin

gle-levelcategoriessho

wnin(a

),an

dafulllisto

fassociatio

ns

isprovided

inSup

plem

entaryTable1.


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HighlightedspecificknownornoveldiseasesassociatedwithLD,analyzedathigherresolutionAlthoughtheCCS-single-levelcategorieswerehelpfulinidentifyingdiseasegroupsofrelevancefromabroaderperspective,wealsoperformedthesameanalysisatahighergranularity(Table1bandS.Table1).Tothisend,usingtheICD-9codes,wesoughttodeterminewhichspecificdiseasesdrovethesignalandwhetherthesignalstillpersisted.Atotalof3,639Lyme–comorbiditycombinationswereanalyzedusingtheICD-9codes.Atthe2-yearwindow,fivepairswerenominallysignificant(p<0.1duetotherelativelysmallsamplesize,N≥20patientsforLymefirstonset),withfourpriortoLDandoneafter(S.Table1).Forthe5-yearwindow,wefound53significantassociations,with49priortoLDand4afterwards.Forthe10-yearwindow,wefound75significantassociations,with67priortoLDdiagnosisand8after.ThesignificanceofalldiseasecategoriessignificantlyassociatedwithLDthatweidentifiedinthepreviousanalysispersisted,includingthefourdiseasesthatsignificantlyoccurredpriortoLD:‘purehypercholesterolemia'(p=0.080,prob=0.54at10years),‘hyperlipidemiaNEC/NOS’(p=0.090,prob=0.54at10years),‘hypertensionNOS'(p=0.082,prob=0.53at10years),and‘coronaryatherosclerosis(athero)NOS'(p=0.022,prob=0.61at5years;p=0.075,prob=0.62at10years).Ninesequelaediseases,namely‘vitaminDdeficiencyNOS'(p=0.014,prob=0.56at5years;p=0.0047,prob=0.57at10years),‘cataractNOS'(p=0.041,prob=0.62at5years;p=0.030,prob=0.62at10years),‘senilenuclearcataract'(p=0.0013,prob=0.85at10years),‘tearfilminsufficiency(insuffic)NOS'(p=0.033,prob=0.67at10years),‘acutebronchitis'(p=0.015,prob=0.65at5years;p=0.017,prob=0.65at10years),‘blepharitisNOS'(p=1.1E-7,prob=0.92at10years),‘unspecifiedabnormalmammogram'(p=0.0083,prob=0.70at5years;p=0.0027,prob=0.72at10years),‘HIVpositiveNOS'(p=0.012,prob=0.72at5years;p=0.0035,prob=0.75at10years)’and‘routinechildhealthexam'(p=3.2E-4,prob=0.71at5years;p=8.8E-5,prob=0.72at10years)drovethesignalfromthebroaddiseasecategories(Table1b).Additionally,wereportedLDcomorbiditiesifothersignificantICD-9codesassociatedwithLDwithalistofcomorbiditiesarenotwidelyknown,including‘insomniaNotElsewhereClassifiable(NEC)'(p=0.042,prob=0.59at5years;p=0.045,prob=0.58at10years),‘obstructivesleepapnea'(p=0.085,prob=0.60at5years;p=0.044,prob=0.62at10years),‘cervicalgia'(p=0.073,prob=0.59at5years;p=0.041,prob=0.60at10years),and‘dysuria'(p=0.096,prob=0.59at5years;p=0.034,prob=0.62at10years). WeconfirmedthatthelargemajorityofthecomorbiditypairsweresignificantlyassociatedwithLDwithconcordantdirectionalitybyadjustingage,gender,andracebylogisticregression(p<0.1).WeprovideacompletelistofICD-9leveldiseaseassociationsthatpassedoursignificancethresholdinbothanalysesSupplementalTable1.


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MedicationspredictedtomodulateriskofsubsequentcomorbiditiesinLDpatients,analyzedasbroaderdiseasecategoriesToinvestigatehowvariousprescribedmedicationsinfluencedtheriskofsubsequentdiseasepathogenesis,wefocusedoncomorbiditieswithonsetafterthefirstdiagnosisofLD.UsingtheadaptiveLASSOmethodologyandalogisticregressionmodel,weinvestigatedallmedicationsprescribedtoLDpatientspriortothecomorbidities.Wefound3,12,and18medicationsassociatedwithdiseasecomorbidities,classifiedbyCCS-single-levelcategories,within2,5,and10yearsafterLymediagnosis,respectively(S.Table2,Figure2a,Figure2b).Fourmedication–Lymecomorbidityassociationsweresupportedbypublishedstudies35-41,andweconfirmedthatthesemedicationsmodulatedtherisksofLymecomorbidities,includingfluticasone–‘cataract’(adjustedOR=1.94,p=0.072at5years;adjustedOR=2.01,p=0.033at10years)hydrochlorothiazide–‘neoplasmsofunspecifiednatureoruncertainbehavior’(adjustedOR=2.23,p=0.031at5years;adjustedOR=2.48,p=0.0092at10years),metformin–‘nutritionaldeficiencies’(adjustedOR=2.05,p=0.097at10years),andesomeprazole–‘nutritionaldeficiencies’(adjustedOR=1.75,p=0.093at10years).Fiveantibiotics,doxycycline,azithromycin,levofloxacin,clavulanate,andmupirocin,andoneantiviraldrug,valacyclovir,werepredictedtomodulatetheriskofsubsequentcomorbidities.Doxycycline,afirst-lineantibioticthatwasthemostprescribedantibioticinourEMRforpatientswithLD(39%,N=553),wasassociatedwithanelevatedriskofeyedisorders,including‘cataract’(adjustedOR=2.05,p=0.092at2years;adjustedOR=1.70,p=0.067at10years),‘blindnessandvisiondisorders’(adjustedOR=2.05,p=0.016atthe5years;adjustedOR=1.95,p=0.019at10years),and‘othereyedisorders’(adjustedOR=1.81,p=0.024)(Figure2a).Inregardto‘nutritionaldeficiencies',elevenmedicationswerepredictedtoberiskfactorsandthreetobeprotective.Amongthe11riskfactormedicationsweretwoantibiotics,levofloxacin(adjustedOR=2.26,p=0.0093at5years;adjustOR=2.77,p=7.0E-4at10years)andclavulanate(adjustedOR=1.64,p=0.094at10years),andoneantiviralprophylactic,valacyclovir(adjustedOR=2.56,p=0.014at5years;adjustedOR=2.58,p=0.011at10years).Additionally,twopainrelievers,diclofenacandhydrocodone,andoneanti-allergymedication,azelastine,werealsoriskfactorsfor‘nutritionaldeficiencies'(respectively:OR=3.08,p=0.0015at5years/adjustedOR=3.02,p=0.0014at10years;adjustedOR=1.90,p=0.034at10years;andadjustedOR=3.44,p=0.0037/adjustedOR=2.95,p=0.0094).Interestingly,wecouldidentifynewtherapeuticoptionsfortheLDadjunctivetreatment.Threemedications,propofol,docusate,andheparin,consistentlyexhibitedaprotectiveeffectagainst‘nutritionaldeficiencies’at5and10yearsafterLD(respectively:adjustedOR=0.32,p=6.6E-4at5years/adjustedOR=0.43,p=0.0044at10years;adjustedOR=0.37,p=0.0039at5years/adjustedOR=0.46,p=0.014at10years;andadjustedOR=0.44,p=0.024at5years/adjustedOR=0.41,p=0.014at10years)(Figure2).Inaddition,acetaminophenexhibitedaprotectiveeffectattheearlystage(2yearspost-Lyme)withadjustedOR=0.44,p=0.0069(S.Table2).


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MedicationspredictedtomodulateriskofsubsequentcomorbiditiesinLDpatients,analyzedattheICD-9levelInthehigher-resolutionanalysisusingICD-9codes,weidentified7,22,and31medicationsthatweresignificantlyassociatedwiththediseasecomorbiditiesat2,5,and10yearspost-Lyme(S.Table3,Figure3aand3b).Amongthesewerepreviouslyreportedriskassociations42-45:forinstance,steroidprednisonewasariskfor‘paininlimb’withadjustedOR=2.16,p=0.030at5years/adjustedOR=2.49,p=0.0063at10years,andciprofloxacinwasariskfor‘jointpain-shoulder(shlder)’withadjustedOR=4.42,p=8.9E-5at5years/adjustedOR=4.39,p=3.1E-5at10years.Inaddition,fiveofthesideeffectsforfourmedicationswerereportedintheSIDERdatabase46,47.Twosteroids,fluticasoneandmometasone,andonepainreliever,hydrocodone,wereassociatedwithincreasedriskfor‘acuteupperrespiratoryinfection(URI)NOS’incomparisonwiththeplacebogroup(Stable3)andwererediscoveredinourstudy(respectively:adjustedOR=2.92,p=5.2E-5at5years/adjustedOR=3.44,p=4.7E-7at10years;adjustedOR=2.86,p=0.0028at10years;adjustedOR=4.01,p=4.1E-5at5years/adjustedOR=4.45,p=1.8E-6at10years).Wealsoreconfirmedtheriskassociationsbetweenfluticasoneand‘chronicrhinitis’(adjustedOR=4.70,p=1.4E-4at2years/adjustedOR=4.78,p=6.5E-7at5years/adjustedOR=4.86,p=4.4E-8at10years)anddiclofenacand‘paininlimb’(adjustedOR=3.43,p=0.0011at10years). DoxycyclineexhibitedaconsistentlyprotectiveeffectagainsttypicalsymptomsofLD,including‘backacheNOS’(adjustedOR=0.44,p=0.018at5years/adjustedOR=0.50,p=0.035at10years)and‘chronicrhinitis’(adjustedOR=0.48,p=0.036at5years/adjustedOR=0.48,p=0.024at10years)(Figure3a,3b).Furthermore,sevenantibiotics,doxycycline,amoxicillin,azithromycin,ciprofloxacin,levofloxacin,mupirocin,andsulfamethoxazole,andoneantiviraldrug,valacyclovir,modulatedtheriskofsubsequentcomorbidities.Doxycyclineconsistentlyincreasedtheriskof‘cataractNOS’(adjustedOR=2.57,p=0.053at2years/adjustedOR=1.89,p=0.058at10years),‘tearfilminsufficNOS’(adjustedOR=2.64,p=0.042at5years/adjustedOR=2.37,p=0.050at10years),and‘nocturia’(adjustedOR=3.46,p=0.010at2years)(Figure3b).Amoxicillin,anotherantibioticrecommendedforLD,increasedtheriskof‘acuteURINOS’(adjustedOR=3.01,p=6.5E-4at2years/adjustedOR=2.41,p=8.4E-4at5years/adjustedOR=2.60,p=1.3E-4at10years).Furthermore,azithromycinwasassociatedwithanincreasedriskofurinary-relateddiseasessuchas‘nocturia’(adjustedOR=4.62,p=3.5E-5at5years/adjustedOR=4.90,p=1.3E-5at10years)and‘urinary(urin)tractinfectionNOS’(adjustedOR=2.18,p=0.0095at5years),aswellasrespiratorydiseasessuchas‘acuteURINOS’(adjustedOR=8.63,p=3.9E-12at2years/adjustedOR=7.55,p=1.0E-16at5years/adjustedOR=7.2,p=1.4E-17at10years),‘acutebronchitis’(adjustedOR=5.15,p=5.9E-5at5years/adjustedOR=4.75,p=1.1E-4at10years),and‘chronicrhinitis’(adjustedOR=2.99,p=7.2E-4at5years;adjustedOR=3.07,p=1.5E-4at10years).Ciprofloxacin,afluoroquinoloneantibiotic,increasedriskof‘nocturia’(adjustedOR=7.19,p=5.9E-6at5years/adjustedOR=6.92,p=7.0E-6at10years)and‘jointpain-shlder’(adjustedOR=4.42,p=8.9E-5at5years/adjustedOR=6.92and


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p=7.0E-6at10years).Mupirocin,anantibioticusedtotreatskininfection,increasedriskofskindisorders,including‘solardermatitisNEC’(adjustedOR=12.93,p=6.9E-10at5years/adjustedOR=13.96,p=3.0E-11at10years)and‘scar&fibrosisofskin’(adjustedOR=11.52,p=6.9E-9at5years/adjustedOR=12.46,p=1.0E-9at10years)(Figure3a,3b).‘VitaminDdeficiencyNOS’,commoninpatientswithpersistentLD48,isaspecificformofnutritionaldeficiency,acomorbidityidentifiedearlieratthebroader(CCS-single)level(Figure2a,2b).Severalmedicationsincreasedtheriskofthiscondition,threeat5yearspost-Lymeandfiveat10years.Theseincludedtwoanti-infectivedrugs,levofloxacin(adjustedOR=2.68,p=0.0012at10years)andvalacyclovir(adjustedOR=1.95,p=0.087at5years/adjustedOR=2.01,p=0.065at10years),azelastine(adjustedOR=3.37,p=0.0035at5years/adjustedOR=2.92,p=0.0085at10years),diclofenac(adjustedOR=2.75,p=0.0032at5years/adjustedOR=2.75,p=0.0026at10years),andsimvastatin(adjustedOR=1.77,p=0.083at10years).Ontheotherhand,fourmedicationsprotectedagainst‘vitaminDdeficiencyNOS’:docusate(adjustedOR=0.33,p=0.0015at10years),propofol(adjustedOR=0.37,p=0.0015at10years),fentanyl(adjustedOR=0.46,p=0.012at5years),andacetaminophen(adjustedOR=0.39,p=0.0025at2years)(Figure3a,3b).Respiratorydisease(Figure3b)isacomplicationfrequentlyreportedafterLD49.Weidentified11medicationsthatincreasedriskfortheseconditionsandtwothatexhibitedprotectiveeffects.InadditiontothethreemedicationsreportedinSIDERdatabaseandamoxicillinandazithromycinabove,themedicationsthatconferredincreasedriskfor‘acuteURINOS’wereanantibiotic,levofloxacin(adjustedOR=3.18,p=9.1E-4at10years),asteroid,methylprednisolone(adjustedOR=2.14,p=0.027at5years/adjustedOR=2.31,p=0.0077at10years),cyclobenzaprine(adjustedOR=3.21,p=0.0025at5years/adjustedOR=2.91,p=0.0037at10years),homatropine(adjustedOR=7.16,p=7.3E-7at10years),atorvastatin(adjustedOR=2.67,p=0.0017at10years),andaspirin(adjustedOR=1.80,p=0.073at10years).Bycontrast,acetaminophen(adjustedOR=0.55,p=0.025at5years/adjustedOR=0.62,p=0.050at10years),andoxycodone(adjustedOR=0.49/p=0.021at10years)wereassociatedwithprotectiveeffectsagainstthisdisease.MedicationsthatmodulateLDpathophysiologyondifferenttimescalesWeidentified16medicationsassociatedwithdiseasecomorbiditieswithin5yearspost-LD,81%(13/16)ofwhichoverlappedwiththoseidentifiedasassociated10yearspost-LymebytheCCS-single-levelcategorization.Specifically,fiveoutofsixanti-infectivedrugs,doxycycline,azithromycin,levofloxacin,mupirocin,andvalacyclovir,appearedinbothtimeframes.Moreover,22medicationswereassociatedwiththeICD-9–leveldiseasecomorbiditieswithin5yearsafterLyme,95%(21/22)ofwhichwerealsoidentifiedinthe10-yearpost-Lymeanalysis.Amongthose21medications,fiveareantibiotics(doxycycline,amoxicillin,azithromycin,ciprofloxacin,mupirocin)andoneisanantiviraldrug(valacyclovir).Thefourmedications


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associatedwithcomorbiditiesexclusivelyinthe5yearspost-Lyme,clavulanate,gabapentin,midazolam,andfentanyl,mayimpactrelativelyearlyLymecomorbidities(S.Figure1).Atotalof17medicationsoverlappedbetweentheCCS-singleandICD-9levelsineitherthe5-yearor10-yeartimewindows.Fiveofthemwereanti-infectivedrugs,namelydoxycycline,azithromycin,levofloxacin,mupirocin,andvalacyclovir.Inthe5-yeartimewindow,16medicationswereassociatedwithcomorbiditiesclassifiedbyCCS-single-levelcategory,ofwhich50%(8/16)werealsoidentifiedattheICD-9level.At10yearspost-Lymediagnosis,weidentified21significantassociationsbetweenmedicationsandcomorbidities,ofwhich81%(17/21)wereconsistentwiththoseidentifiedattheICD-9level.Survivalanalysisoffirst-linemedicationsinpropensity-matchedpopulationsBythecross-sectionalanalysisdescribedabove,wedemonstratedthatcertainmedicationsincreasedriskorprotectedagainstdiseasecomorbiditiesinpatientswithLD.Athigherresolution(i.e.,usingICD-9codes)with10-yearfollowup,wefoundthatdoxycycline,themostcommonlyusedantibioticfortreatmentofLD13,protectedagainst‘backacheNOS’and‘chronicrhinitis’,butincreasedriskof‘tearfilminsufficNOS’and‘cataractNOS’.Anothercommonlyusedantibiotic,amoxicillin,wasassociatedwithelevatedriskof‘acuteURINOS’. Priortopropensityscorematching,weidentifiedsignificantdifferencesinthedistributionsofdemographicandclinicalcharacteristicsbetweenthedoxycycline/amoxicillin-treatedanduntreatedgroupsbefore.Thedoxycycline-treatedgroupwassignificantlyolderthantheuntreatedgroup(P<0.007),whereastheamoxicillin-treatedgroupwassignificantlyyoungerthantheuntreatedgroup(P=8.7E-4).Inaddition,doxycyclinewasprescribedmorefrequentlytomalethanfemalepatients(P<0.03).Thedoxycycline/amoxicillin-treatedgroupshadhigherprevalencesofcertainpre-existingcomorbiditiesandahigherprescriptionrateofparticularmedicationsthantheuntreatedgroups(S.Table4).Moreover,boththedoxycycline/amoxicillintreatedgroupshadhigherpropensityscoresthanthecorrespondinguntreatedgroups(P<0.001).Toclarifythelongitudinaleffectsofdoxycyclineandamoxicillin,weanalyzedtheseassociationsbypropensity-score-matchedsurvivalanalyses.Afterpropensityscorematching,thecontrolcohortswerewellbalancedwiththetreatedgroupsintermsofobservedcovariates(S.Table4).Thisanalysisrevealedthattheriskof‘backacheNOS’(Figure4a)and‘chronicrhinitis’(Figure4b)wassignificantlylowerinthedoxycycline-treatedcohortthanintheuntreatedcohort(HR=0.42,p=0.020;HR=0.49,p=0.040,respectively;Table3).Furthermore,Kaplan-Meiercurvesdemonstratedthatthecumulativeprobabilitiesofremainingfreefrom‘cataractsNOS’and‘tearfilminsufficNOS’wereloweramongdoxycycline-treatedpatients(p=0.0672and0.0608,respectively;Figures4cand4d).Coxregressionanalysissupportedastatisticallysignificantassociationbetweendoxycyclineusageandincreasedriskofboth‘cataractNOS’and‘tearfilminsufficNOS’(HR=1.90,p=0.072;HR=2.65,p=0.071).Ontheotherhand,patientsprescribedamoxicillinhadsignificantlyhigherhazardratiosfor‘acuteURINOS’(HR=2.26,p=0.0091;Figure


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4e).Therefore,theeffectsofdoxycyclineandamoxicillinrevealedbythecross-sectionalanalysiswereconfirmedbysurvivalanalysesusingthepropensityscore-matchedcohort(Table3).

Medication Disease(ICD9) ICD9Pvalue(LogRank)

HazardRatio(90%CI) Pvalue(Cox)

DoxycyclineTearfilminsufficNOS 375.15 6.08E-02 2.65(1.09-6.45) 7.13E-02

Doxycycline CataractNOS 366.9 6.72E-02 1.9(1.06-3.42) 7.18E-02Doxycycline Chronicrhinitis 472.0 3.60E-02 0.49(0.28-0.87) 3.99E-02Doxycycline BackacheNOS 724.5 1.67E-02 0.42(0.23-0.78) 2.03E-02Amoxicillin AcuteURINOS 465.9 7.41E-03 2.26(1.35-3.78) 9.13E-03

Table2Survivalanalysesoffirst-linetherapeuticsforLymediseaseusingapropensity-score-matchedcohort.


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DISCUSSIONProperdiagnosis,treatment,andmanagementofLymeDisease(LD)aredifficultforavarietyofreasons.Inparticular,thecomplexinterplaybetweenvarioustreatmentsandcurrentclinicalstatus,includingdiseaseburden,canleadtoawiderangeofsequelae.Thisstudyrepresentsthefirstdata-drivenefforttoidentifyclinicalfactorsthataffecttreatmentofLDpatientsusinglarge-scaleEMRdata.EMRsystemscontaininformationpertainingtopatients'healthovertime,includingtreatmentsadministeredandclinicaloutcomes.Thus,oneadvantageofusingthesedataincomparisonwithprospectiveclinicaltrialstudiesistheavailabilityoflongitudinaldataspanningmorethan10years,increasingthelikelihoodofcapturinglong-termeffects.Weutilizedstatisticalandmachinelearninganalysestoidentifyassociationsbetweenmedications,includingfirst-linetreatments,andcomorbiditypathogeneses.Incontrasttoone-size-fits-allstrategies,ourapproachmayfacilitatethepersonalizationoftreatmentregimensbasedontheclinicalprofilesofaffectedindividuals.Thisstrategictransitionisessentialinlightofthetremendousvariabilityinefficacyofantibioticsandtheadverseeventsassociatedwiththesetreatments. WefirstidentifiedallsignificantcomorbiditiesofpatientswithLDbeforeandaftertheirLymeinfections.Next,weappliedmachinelearningmodelstoassesstheeffectofmedicationtreatmentontheriskofdevelopingsubsequentconditions.Ouranalysesidentifiedknownassociationsbetweenmedicationsandspecificdiseasecomorbidityoutcomes,andalsodiscoveredconnectionsbetweendrugsandLDthatcouldfacilitateprecisionmedicineaimedattailoringtreatmentstoaffectedindividuals'Lymesymptomprofile. Ouranalysisidentifiedco-morbidconditionsthatweretypicallypresentbeforeLDinfection.Althoughthisdiseaseclearlyrequirescontactwiththebacteria,certainphysiologicalpropertiesmakeindividualsmoreorlesssusceptibletoinfection.Forexample,wefoundthatindividualscategorizedashaving‘disordersoflipidmetabolism’weremorelikelyhaveLDinfectioninthefuture.Borreliaburgdorferirequirescholesterolforgrowth;researchershavefoundthatapolipoproteinE(apoE)-deficientandlow-densitylipoproteinreceptor(LDLR)-deficientmice,whichhavehighlevelsamountsofserumcholesterol,aremoresusceptiblethanwild-typemicetopathogenesisinducedbythisbacterium34.Additionally,patientswithhypercholesterolemiacouldincreasesusceptibilitytotriggertickbiteforthisvectorbornediseaseduetobodyheat,CO2,andmoisturewhicharekeyattractantssimilarlytomosquitoes50 51,butthisisbeyondthescopeofthisanalysisandneedstobefurtherinvestigated.Additionally,weidentifiedanassociationbetweenHIVinfectionandLD.Specifically,ourdatashowedthatpatientswithHIValmostexclusivelydevelopedLDsubsequenttotheHIVdiagnosis,suggestingthatimmunesystemalterationincreasestheriskofLD.AhandfulofcasereportshaveindicatedthatHIV-positiveimmunocompromisedpatientsdevelopmoresevereLymecomplicationsfollowinginfection52-54.Althoughthespecificimmunologicalmechanisms


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drivingthisconnectionremainunclear,itseemsreasonabletospeculatethatimmunosuppressionplaysanimportantrole55.WealsoidentifiedconditionsthataremorelikelytobepresentafteraLDdiagnosisthanbeforehand,consistentwiththepossibilitythatthesediseasesaresideeffectsorcomplicationsarisingfromLymeinfection.Manyoftheseassociationsarewelldocumented,enhancingourconfidenceinourresults.Specifically,wefoundthatthecategories‘nutritionaldeficiencies’,‘cataract’,‘acutebronchitis’,‘othereyedisorders’,and‘Inflammation;infectionofeye(exceptthatcausedbytuberculosisorsexuallytransmitteddisease)’aremorelikelytooccurafterLymeinfectionthanbeforehandorbychance. Theresultsofthisanalysisfeedintoourdrug-comorbidityassociationsnetworkandcanbeusedtoinformtreatmentregimens.Theassociationsidentifiedforfirst-lineantibiotictreatmentsofLDhavethemoststraightforwardpotentialapplication.TheseagentsactbykillingB.burgdorferi,andthuspreventthedevelopmentofmanycomplicationsassociatedwithprolongedexposuretothebacteria.However,whileantibioticsarethemosteffectivefirst-linetreatmentsforLD,theirefficaciesarenonethelesslimited;moreover,somesymptomsmaypersistnotwithstandingtheuseofantibiotics,andlong-termexposuretotheseagentsrisksadditionalcomplications.Indeed,itispossiblethatevenacuteuse(usuallyamonth)ofthesetreatmentsisassociatedwithlong-termcomplicationsofLDthatyettobedetermined.Evenwhentreated,upto20%ofpatientsdevelopPost-TreatmentLymeDiseaseSyndrome(PTLDS),inwhichsymptomsincludingfatigueormusclepainlastformonthsoryears.AlthoughtheetiologyofPTLDSisnotyetknown,bettertailoringoftreatmentstrategiestoanindividual’sphenotypicprofilecouldpreventormodulatetheriskofdevelopingthesesymptoms.WeidentifiedanumberofcomorbiditiesmatchingthesymptomsalignedwithPTLDS,includingchronicpain,chronicrhinitis(Figures3aand3b).Notablyinthisregard,wealsofoundthatusageofsteroidmedicationsincreasestheriskofmanysymptomscommontoPTLDS.Consistentwiththis,corticosteroiduseisassociatedwithpooroutcomesforLDpatients43.Inparticular,wefoundthatprednisonewasassociatedwithelevatedriskfor‘backacheNOS’,‘paininlimb’and‘otherabnormalglucose’,definedattheICD-9level.Useoffluticasonewasassociatedwithelevatedriskfor‘chronicrhinitis’,‘postnasaldrip’,‘cervicalgia’,and‘acuteURINOS’;mometasonewasalsoassociatedwithelevatedriskfor‘acuteURINOS’;andmethylprednisolonewaslinkedtoincreasedriskof‘chronicrhinitis’,‘backacheNOS’,and‘acuteURINOS’aswell.Steroids,whichsuppresspatients’immunesystems,mightbeparticularlyharmfultoLDpatients,allowingthebacteriatogrow,ratherthanattackingtheinfections.ThesefindingssuggestthatsteroiduseshouldbelimitedinLDpatients,andthatpatientsexposedtothesedrugsshouldbemonitoredcarefullyforcomplications. Otherfindingsfromourdrug-comorbiditynetworkmightfacilitatepersonalizationoftreatmentregimens,withmorefavorableclinicaloutcomesforpatients.Forexample,severalanti-infectiousdrugs,painrelieverssuchasdiclofenacandhydrocodone,andtheanti-allergymedicationazelastinewerealsoassociatedwithhigherratesof‘nutritionaldeficiencies’,


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21

suggestingthatphysiciansshouldconsiderrecommendingvitaminsupplementsforpatientsreceivingthesetreatments. Doxycyclineisalreadyassociatedwitharangeofsideeffects,includingpain,increasedpressureinsidetheskull56,andgastrointestinalinjury57.Thenuancesoftheseassociationsarenotwellunderstood.Ontheotherhand,wealsofoundthatdoxycyclineusewasassociatedwithlowerriskof‘backacheNOS’andlowerratesof‘chronicrhinitis’;thelatteristobeexpected,asitisacommonsymptomofchronicLD11.Thismedicationincreasedtheriskofmanyeye-relatedissues,suchas‘cataractNOS’,withthe2-and10-yeartimewindows,suggestingthatitmightexertbothshort-termandlong-termsideeffects.Wealsofoundassociationsbetweenthismedicationandelevatedriskfor‘tearfilminsufficNOS’and‘blindnessandvisiondisorders’. Thedevelopmentofrespiratory-relatedcomplicationsisamajorconcernforpatientsinfectedwithLD.Inonecasestudy,secondaryadultrespiratorydistresssyndromecausedthedeathofapatientaffectedwithLDduringthecourseofher2-monthtreatment58.Thepatientdidnotrespondtoconventionaltreatments,includingantibiotics,salicylates,andsteroids.Inourstudy,weidentifiedmedicationsthatareassociatedwithelevatedriskofrespiratory-relateddiseases.Specifically,wefoundthattheantibioticsamoxicillin,levofloxacin,andazithromycinallconferredincreasedriskof‘acuteURINOS’.Inadditiontotheknownrisksoftwosteroids,prednisolone,andmometasone,reportedintheSIDERdatabase(Stable3),wefoundthatanothersteroid,methylprednisolone,wasalsoassociatedwithincreasedriskforthisdisease.Whileweareunabletoinfercausationfromouranalyses,theassociationsweidentifiedwillhopefullyinformphysiciansoftherisksandencouragethemtotaketheappropriateprophylacticmeasures.ParticularattentionshouldbepaidtoLymepatientswithrespiratorycomplicationsbecausetheirimmunesystemsarealreadyweakenedfromLymeinfection,andcertainmedications(suchasamoxicillin)areineffectiveattreatingtheseinfections59.Thisstudyhadseverallimitations.Oneissueistherelativelowsamplesize,whichisaconsequenceoftherarityofthisdiseasealthoughourhospitalhasthelargestEMRsysteminNYC.BasedontheavailableELISAandWesternblotlabtestsspecificforIgMandIgG,wefoundagreatconcordanceforpositiveserologyinpatientswithLymeICDcodes,whichenhancedourconfidenceofidentifyingtruepositiveLDpatients.Basedonlimitedavailabilityofthesedata,however,wehadtousetheICD-9codealonetoselectthepatientcohortinthisstudy.Astickbitesaremostlikelytooccurinsurroundingrurallocationsinwhichforestsarepresent,manypatientsmaybeinitiallydiagnosedinadifferentfacility,andthencometoMSHforfollow-uptreatment.AnotherlimitationisrelatedtothecloseproximityofMSHtoothermedicalcentersinthearea.Specifically,patientsmayseektreatmentatothernearbyhospitals,resultinginthelossofvaluableinformationfromourEMRsystem.Finally,becausewedonothaveaccesstopatients'historicEMRdatafromoutsideofMSH,ourtemporalanalysesmaynotaccuratelycapturethetruetimelineofacquisitionofdiseasecomorbidities.Wearecurrentlyperforming


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anexternalreplicationanalysisatanotheracademicmedicalcenter,andtheresultsofthiseffortmaybolsterourconclusions.Additionally,weareapplyingthefindingsfromourcurrentstudyinordertomodelexplicit,optimaltreatmentrecommendationsatthepatientlevel.Fromthiswork,wehopetoenhancenotonlythesuccessratesoftreatmentofLD,butalsotofacilitatepreemptivestrategiesformanaginghigh-riskensuingconditions.OurstudyisthefirsttoinvestigateacomprehensiveandraciallydiverseEMRwiththeaimofdiscoveringthedetailedclinicalprofilesofpatientsbeforeandafterdiagnosisofLD.Weidentifiedalistofmedications,includingantibioticsrecommendedfortreatment,whichrepresentpossibleriskfactorsforchronicLDorPTLDS.Inaddition,wehopetoinvestigatethecontributionsofgenomicsandgeneticvariantstodifferencespathophysiology.Ourpredictivemedication–comorbiditymodelsprovideanevidence-basedapproachfortreatmentregimensthattakesintoaccountriskforLymecomorbidities,withtheultimategoalofguidingprecisionmedicinebasedontheindividualclinicalphenotypesofpatientswithLD.


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CONTRIBUTORSLLandJDwereresponsibleforinitialstudydesign.LLwasresponsiblefordatacollection.OI,BG,andLLwereresponsibleforstudyimplementation,interpretingthedata,andongoingmanagement.OIandBGwereresponsibleforstatisticalanalysis,predictivemodels,literaturereview,andgeneratingtablesandfigures.OI,BG,LL,andJDandwroteandeditedmanuscript.BKprovidedHIVinsightsandedits.LLandJDsupervisedthestudy.DECLARATIONOFINTERESTSDr.DudleyhasreceivedconsultingfeesorhonorariafromJanssenPharmaceuticals,GlaxoSmithKline,AstraZeneca,andHoffman-LaRoche;isascientificadvisortoLAMTherapeutics;andholdsequityinNuMediiInc.,AyasdiInc.,andOntomics,Inc.Dr.IchikawaisanemployeeofSumitomoDainipponPharmaCo.,Ltd.Therestofauthorsdeclarenocompetinginterests.ACKNOWLEDGEMENTSThisstudywasfundedbytheSteven&AlexandraCohenFoundation.WethankSaviGloweandFranciscoSantiagoforadministrativesupport.WethankDr.ChristopherPatilforprovidingscientificedits.WethankMountSinaiDataWarehouseforsupportingdataaccess.REFERENCES1. Nelson CA, Saha S, Kugeler KJ, et al. Incidence of Clinician-Diagnosed Lyme Disease,

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31. Cristea V, Crisan M. Lyme disease with magnesium deficiency. Magnes Res 2003;

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48. Donta ST. Issues in the diagnosis and treatment of lyme disease. Open Neurol J

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49. Abbott RA, Hammans S, Margarson M, Aji BM. Diaphragmatic paralysis and

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53. Bremell D, Sall C, Gisslen M, Hagberg L. Lyme neuroborreliosis in HIV-1 positive men

successfully treated with oral doxycycline: a case series and literature review. J Med Case

Rep 2011; 5: 465.

54. van Burgel ND, Oosterloo M, Kroon FP, van Dam AP. Severe course of Lyme

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57. Affolter K, Samowitz W, Boynton K, Kelly ED. Doxycycline-induced gastrointestinal

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59. Little P, Stuart B, Moore M, et al. Amoxicillin for acute lower-respiratory-tract

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FigurelegendsFigure1Workflowofthestudy,outliningstepsfromdataorganizationtostatisticalmethodologies.Figure2Medication–Lymediseasecomorbiditynetwork,analyzedbyCCS-single-levelcategories,intimewindowsof5years(a)and10years(b).Significantassociationsbetweenmedications(cyan)andcomorbidities(magenta)areconnectedbyredorbluelines(p<0.1).Redlinesindicateriskassociations(OR>1),andbluelinesindicateprotectiveassociations(OR<1).Medicationsandindications(green)wereconnectedbasedoninformationinthepublicknowledgebaseMEDI60.Figure3Medication–LymediseasecomorbiditynetworkattheICD-9levelsintimewindowsof5years(a)and10years(b).Significantassociationsbetweenmedications(cyan)andcomorbidities(magenta)areconnectedbyredorbluelines(p<0.1).Redlinesindicateriskassociations(OR>1),andbluelinesindicateprotectiveassociations(OR<1).Figure4Kaplan–Meierplotofpropensity-score-matchedsurvivalanalysis(a)doxycycline–‘backacheNOS’(ICD-9code:724.5),(b)doxycycline–‘chronicrhinitis’(472.0),(c)doxycycline–‘cataractNOS’(366.9),(d)doxycycline–‘tearfilminsufficNOS’(375.15),and(e)amoxicillin–‘acuteURINOS’(465.9).Supplementaryfigure1Venndiagramofthemedicationsthatsignificantlyassociatedwithatleastonediseasecomorbidityinthe5-and10-yeartimewindows.(a)CCS-single-levelcategories.(b)ICD-9level.SupplementarytableS1AlldiseasesassociatedwithLyme,byICD-9category(pvalue<0.1).SupplementarytableS3Medicationspredictedtomodulateriskofdiseasecomorbidities,byCCS-single-levelcategory(pvalue<0.1).SupplementarytableS4Medicationspredictedtomodulateriskofdiseasecomorbidities,byICD-9category(pvalue<0.1).SupplementarytableS5Thebalanceofcovariatesbeforeandafterpropensityscorematching.


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Mount Sinai HospitalEMR

Lyme Disease Cohort

Clinical Classification Software (CCS)RxNorm

n = 1,767

Disease diagnoses (Dx)Medication prescriptions (Rx)

Adaptive Lasso

Lyme

Feature Selection

Logisitc Regression

Cross-sectional Analysis

Dx Temporal Directionality

Propensity Score Matching

Temporal Analysis

Survival Analysis

Time Window

Filtering

A

with medication data>7 days follow-up n = 1,196

BICD-9 = 088.81

n = 2,134

Diagnosed year ≥ 2000n = 1,787

Defined age, sex, racen = 1,767


https://doi.org/10.1101/239020


CataractBlindness and vision defects Nutritional deficiencies

Neoplasms of unspecified nature or

uncertain behavior Other eye disorders Nonmalignant breast

conditions Acute bronchitis

Diseases of the nervous system and sense

organs

Diseases of the respiratory system

Diseases of the circulatory system

Diseases of the digestive system

Diseases of the genitourinary system

Injury and poisoning

Diseases of the skin and subcutaneous tissue

Diseases of the musculoskeletal system and connective tissue

Infectious and parasitic diseases

DoxycyclineValacyclovirHeparin Levofloxacin DiclofenacClavulanate GabapentinAzelastineDocusate Propofol Midazolam Prednisone Fluticasone Azithromycin Hydrochlorothiazide Mupirocin

Neoplasms

Symptoms; signs; and ill−defined conditions

and factors influencing health status

Mental illness

Residual codes; unclassified; all e codes

Endocrine; nutritional; and metabolic diseases and immunity disorders Diseases of the blood

and blood−forming organs

-

+

Logarithm of the odds ratio

Common drugs with ICD-9 results*

Indication of drug

Lyme comorbidity

Drug

Anti infectious drug

* ***** **


https://doi.org/10.1101/239020


Azelastine Tuberculin Folic acid Metformin DoxycyclineHydrocodoneEsomeprazole

Neoplasms of unspecified nature or

uncertain behavior

Inflammation; infection of eye (except that

caused by tuberculosis or sexually

transmitteddisease)

CataractNutritional deficiencies Blindness and vision defects Acute bronchitis

Diseases of the respiratory system

Diseases of the skin and subcutaneous tissue

Infectious and parasitic diseases

Diseases of the genitourinary system

Diseases of the musculoskeletal system and connective tissue

Diseases of the circulatory system

Diseases of the digestive system

LevofloxacinDocusateHeparin Valacyclovir DiclofenacPropofol Fluticasone Prednisone Acetaminophen Mometasone Albuterol Azithromycin Hydrochlorothiazide Mupirocin

Symptoms; signs; and ill−defined conditions

and factors influencing health status

Injury and poisoningDiseases of the nervous

system and sense organs

Mental illness

Endocrine; nutritional; and metabolic diseases and immunity disorders

Residual codes; unclassified; all e codes

Neoplasms

Diseases of the blood and blood−forming

organs

-

+


Common drugs with ICD-9 results

** **

*

* ** **** *** ***

Indication of drug

Lyme comorbidity

Drug



https://doi.org/10.1101/239020


Albuterol

Hydrocodone Amoxicillin

Joint pain−shlder

Postnasal drip

Acute URI NOSExt asthma w/o stat asth

Acetaminophen

Cyclobenzaprine

Pain in limbUrinary frequency

Mupirocin

InsomniavaTretinoin Solar dermatitis NEC

Scar & fibrosis of skin Zolpidem

Abn blood chemistry NEC

Alprazolam

Atorvastatin

Other abnormal glucose

Backache NOS

Prednisone

Cervicalgia

Fluticasone

Nocturia

Doxycycline Urin tract infection NOSAcute bronchitis

Methylprednisolone

Tear film insuffic NOS

Chronic rhinitisAzithromycin

Ciprofloxacin

Esomeprazole

Amlodipine

DiclofenacFentanyl

Valacyclovir

Vitamin D deficiency NOS

Azelastine

-

+


Lyme comorbidity

Drug



https://doi.org/10.1101/239020


Aspirin

Atorvastatin

Acute bronchitis

Nocturia

Cyclobenzaprine

Acetaminophen

Homatropine

Abn blood chemistry NEC

Amoxicillin

Postnasal drip

Azithromycin

Mometasone

Acute URI NOSHydrocodone

Levofloxacin Oxycodone

Ext asthma w/o stat asth

Esomeprazole

Sulfamethoxazole

Urin tract infection NOS

Joint pain−shlder

Urinary frequency

Ciprofloxacin

Tretinoin Scar & fibrosis of skin

Alprazolam ZolpidemSolar dermatitis NEC Mupirocin

Insomnia NEC

Pain in limb

Azelastine

Diclofenac

Other abnormal glucose

Prednisone Albuterol

Hydrochlorothiazide

Vitamin D deficiency NOS

Simvastatin

Fluticasone

Amlodipine

Backache NOS

Tear film insuffic NOS

Doxycycline Cervicalgia

Methylprednisolone

Cataract NOS

Chronic rhinitis

Chronic pain NECValacyclovir

Propofol

Docusate

Dysuria

-

+


Lyme comorbidity

Drug



https://doi.org/10.1101/239020


Doxycycline –

Doxycycline +

Doxycycline –

Doxycycline +

Doxycycline –

Doxycycline +

Doxycycline –

Doxycycline +

Amoxicillin –

Amoxicillin +

a b

c d

e


https://doi.org/10.1101/239020


learning and mapping lyme disease patient trajectories ... · 12/23/2017 · comorbidities and...

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