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") '"(.)/*+031 2*34,-5,7<,>68=?ABCDGQR$$b$=L\bt-A8$$$$$$b$)bio*Y~w 0e0e    f A@ A5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||# "0e@        @ABC DFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN 5%  N 5%  N    5%    !"?N@ABC DFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab f3ff@ff; ʚ;G(ʚ;g4ddddCм`fppp@ <4!d!d0ׄgʚ;<4dddd0ׄgʚ; <4KdKd0ׄʚ;g4?d?dCмLpH p___PPT10:     AOH/X  ___PPT9:     A0MO/  h___PPT2001D<4XT___PPTMac11.@f   hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography  :p   hnamd` Arial&Monotype Typographyff A   hnamd` Arial&Monotype Typography OT   hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography /\   hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography    hnamd` Arial&Monotype Typography ? ,O  =BRZ5Motivation: Severity of ProblemClinical trials do not test a broad population Adverse Drug Events (ADEs) world-wide problem *Expense from ADEs is $5.6 billion annually *Estimated that over 2 million patients hospitalized due to ADEs *ADEs are fourth leading cause of death ^ZZ,ZZAZZ(ZZZZ^f+ f@  f'$$((,,00PE$V%6%Motivation: Limitations of ApproachesManual review of case reports (Venulet J 1988) Spontaneous reporting to designated agency (Evans JM 2001; Eland IA 1999; Wysowski DK 2005) Serious ADEs reported less than 1-10% of time Reporting is voluntary for physicians/patients Recognition of ADEs is highly subjective Difficult to determine cause of ADE Biased by length of time on market and other factors Cannot determine number of patients on drug or percent at risk Drug prescribing/claims data (Hershman D 2007; Ray WA 2009) ZZ<ZZZZ,0    $$((,,bR _ KSeverity of Under Reporting  Study showed 87% of time physicians ignored patient reports of known ADEs (Golumb et al. Physicians response to patient reports of adverse drug effects. Drug Safety 2007) Nf,I DocumentSummaryInformation8D Current User&DY7 Related WorkAutomated methods mainly based on spontaneous reporting databases Most methods use (Evans SJ 2001; Szarfman A 2002) Surrogate observed-to-expected ratios Incidence of drug-event reporting compared to background reporting across all drugs and events Some research aimed at improving effectiveness of SPR databases Create ontology of higher order adverse events MedDRA Avoid fragmentation of signalB2@/B  @/ $$>c o8 Related WorkPharmacoepidemiology databases used to confirm suspicions General practice research database (GPRD) (Wood & Martinez 2004) New Zealand Intensive Medicines Monitoring (IMMP) (Coulter 1998) Medicine Monitoring Unit (MEMO) (Evans et al. 2001) EHR databases used to find signals (Brown JS et al. 2007; Berlowitz DR et al. 2006; Wang X et al. 2009) Mainly coded data used Has potential for active real time surveillance Should reduce biased reporting;ZZZhZfZ;*3 !# E$$((,,O00$ J Related WorkConsortiums involving multiple EHRs EU-ADR project (http://www.alert-project.org/) eHealth initiative (http://www.ehealthinitiative.org/drugSafety/) Related work using EHR to detect known ADEs  not aimed at discovering novel ADEs (Bates DW 2003; Hongman B 2001)R$rR%$rW   ,*!  4Q g4'Exploiting the Electronic Health Record3"The Electronic Health Record (EHR)Rich source of patient information Mostly untapped Primary use for EHR Documenting care in multi-provider environment Manual review by providers More complete than coded ICD-9 codes Symptoms Clinical conditions not beneficial for billing Fragmented Heterogeneous Noisy lHK%8 HK%8   :"Research Opportunities: NLP IssuesOccurrence of clinical events in natural language Drugs, diseases, symptoms Temporal information is critical Irregularity of reports Section headings important but abbreviated/missing Use of indentation, lists, run on sentences Tables & semi-structured data in reports Abbreviations 2/2 meaning secondary to co meaning cardiac output or complaining of Mapping terms in text to an ontology/controlled vocabulary infiltrate in chest x-ray means chest infiltrate ontology terms more limited than language 2P<PPPPPEPP;P\PPPPP2<  f  $$((,,0044;88 <<ff)  fPd: %/;*Research Opportunities: Statistical IssuesFind associations between drug, symptoms, and diseases Not explicit in EHR Large volumes of data Statistical significance vs. clinical significance Statistical associations  not relationships Drug treats condition / Drug causes condition Integrating time sequences is important For treats: condition must precede drug event For causes: drug event must precede condition7@@3-.(\73 -  $$(((,,00f(4488f$<<>*Research Opportunities: Statistical IssuesConfounding (indirect associations) Metolazone treats heart failure (HF) HF is manifested by shortness of breath (SOB) Metolazone and SOB indirectly related Higher order associations Drug interactions: Drug1, drug2, condition Drug-contraindications: Drug, disease, condition Rare ADEs$ZzZZ\Z Z$       $$((,,004488<<= 6$ H <4Other Research Opportunities: Knowledge Acquisition55|Structured Knowledge bases UMLS relations (may_be_treated_by) Proprietary ones  usually unavailable Text/Semi-Structured Knowledge (need NLP) Spontaneous reporting databases: indications, drugs, adverse events Literature (Medline) Web sites (WebMD, Micromedix) Online medical textbooks Claims Data (Health IT payors)fK*f* *>+ 2_ %Text Mining for Knowledge Acquisition&&ff% [Statistical methods: co-occurrences Discovered associations between diseases and diets from literature (Weeber M 2002) Identified disease candidate genes ( Hristovski D 2005) NLP systems Trends in medications based on the literature and narrative clinical reports (Chen ES 2007, 2008) Semantic relations in the literature (Hristovski D 2006) % %D &  N $$%((,,00>i-   96Overview of Our NLP-EHR based Pharmacovigilance System?"Natural Language Processing of EHR =ACoded Output from NLPmed:tegretol xr sectname>> report medication item code>> UMLS:C0592163_Tegretol XR med:zocor sectname>> report medication item code>> UMLS:C0678181_Zocor ......... problem:mitral valve regurgitation sectname>> report past history item code>> UMLS:C0026266_Mitral Valve Insufficiency & & .. problem:rib fracture date>> 2001 sectname>> report past history item0PuGJ? }  E Coding Issues6Not all conditions have codes Non-communicative Some conditions are combinations of codes Difficulty sleeping Vascular injury Granularity of coding system Many different codes for a concept Asthma: asthma exacerbation, asthma disturbing sleep, moderate asthma, suspected asthma, & +$#[f)  f$f#[f  f@Standardizing Coded Data B>Standardizing Coded EHR Data: Laboratory Tests and Medications??Lab values denoting normal/abnormal vary Abnormal range may depend on age, sex, ethnicity, weight Change in lab values and duration must be considered Standardizing medications is complex & requires additional knowledge Tradename to generic (Avandia rosaglitazone) Handling of combination medications 1.5% Lidocaine with 1:200,000 Epinephrine Handling of dose & Route Diazepam 2 MG Oral Tablet )oES*)oE  fff%*  f$$((f,,f00   + 4  CSelecting and Filtering DSelecting and FilteringDependence on accuracy of semantic classification UMLS classification errors - Finding: birth history, cardiac output, divorce + Finding: cardiomegaly, fever Temporal information difficult to obtain An adverse drug event should only follow drug event Processing of explicit time information is complex and vague Yesterday, last admission, 2/5 Information typically occur in reports without dates 2U)q520  "f)qf4  $$f((f, FDetect AssociationsGDetect AssociationsICorrect temporal sequence is critical Drug event should precede adverse event Dates are not usually stated along with events Section of reports helpful surrogate Statistical associations correspond to different clinical relations For pharmacovigilance: Want drug causes adverse event Confounding caused by dependencies in data &Z}ZDZZ Z+ZZ&}D fff +$$((N"10HReduce ConfoundingIReduce ConfoundingCollect knowledge from external sources and associations Drug-treat-disease Disease-manifested by-symptom Drug-interacts with-drug Use Information theory Mutual Information (MI) Data processing inequality MI3 < (MI1, MI3) n9ZKZZ3ZZZ9f  f  $$f((,,0044f88<<3   $$((LInitial Study: Methods6 drugs chosen Ibuprofen, Morphine, Warfarin: longtime on market with known ADEs Bupropion, Paroxetine, Rosiglitazone: ADEs discovered after 2004 1 drug class: ACE inhibitors 25,074 textual discharge summaries in 2004 from NYPH processed using MedLEE NLP Reference standard created using expert knowledge sources Drug-potential ADE pairs determined Recall/precision calculated Qualitative analysis performed to classify drug-potential ADE pairs detected ZZZb$_ b bGb9 b $$             3  = 9 MInitial Study: ResultsQuantitative recall (.75), precision (.30) Qualitative analysis: potential drug-ADE pairs Known drug-ADEs: 30% Drug-indication pairs: 30% Remote drug-indication pair: 33% Unknown clinical associations: 6%  /t  /  f P b gN  h"Study 2: Reduction of Confounding ##Evaluation set 14 associations related to 2 drugs from Study 1 Reference standard Drug-ADE associations determined and MI, DPI used to automatically classify them^0db/b  R> e.Results * f$fPPrecision 0.86 when handling confounding 0.31 when without handling confounding. F `F`P q+Discussion: Limitations & Future Directions,,dffMutual information only strategy to handle confounding More complex MI strategy will be explored Other statistical/knowledge based methods will be explored Inpatient data only/sicker patient population The same methods could be used for outpatient data as well - possibly more noisy Drug dosage, drug-drug and more complex interactions should be explored 7g.QI7g.Q  It)IO+Discussion: Limitations & Future Directions,,df+Small evaluation data set More comprehensive evaluation Limitations inherent from NLP, coding, association detection Limitations due to fragmented/incomplete patient data ZZZvZ= 5` .u6 rSummaryf$fiNeed for more pharmacovigilance research Based on the EHR Using available databases and text Studies demonstrated promising results Many interesting research opportunities Natural language processing Statistical methods Integrating different sources of data Gathering knowledge from different sources Automated knowledge acquisition for evidence based medicineN*4O*4O ,@/Acknowledgementf NLP Data Mining group at DBMI at Columbia George Hripcsak Marianthi Markatou Herb Chase Xiaoyan Wang David Albers Jung-wei Fan Lyudmila Shagina Noemie Elhadad Grants R01 LM007659 from NLM R01 LM008635 from NLM R01 LM06910 from NLM 5T15LM007079 from NLM training grant *ZuZZhZ*.   ,   $b$0((d1   3  0/D aitu  (` ` ̙33` 333MMM` ff3333f` f` f` 3>?" dd@ ~?" dd@  " @ ` n?" dd@   @@``PR    @ ` ` p>> f^(    6@ E  T Click to edit Master title style! !  0    RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S   X ?f ? Base"6@ NNN?Npp  f   C 0A dbmi_logo_1"Voj  c 4AW \cu_logo"V  0SJ "^_   l(*July 21 - AIME 2009b  <v޽h @ ?"` ̙33___PPT10q.+D=' = @B + Default Design( 8(     N!gg j!   v* D""DDff  N!gg  !  x* D""DDffd  c $ ?1'  4  N!gg  d  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  T!gg mj   v* D""DDff  T0'!gg m   x* D""DDffH  0%j ? 3380___PPT10.`$ h((  h h N! a a j!   \* 999VVss h N! a a  !  ^* 999VVss h Tp! a a mj   \* 999VVss h T! a a m   ^* 999VVssH h 0%j ? 3380___PPT10. @|  0hD(  hg h c $"_  Q Carol Friedman, PhD Department of Biomedical Informatics Columbia UniversityT:   b :  :U  h <f ?"6@ NNN?N% oDiscovering Novel Adverse Drug Events Using Natural Language Processing and Mining of Electronic Health Records pxp B  h <Df>?"0@NNN?N.5B h <DV?"0@NNN?No|H h 0޽h ? ̙33___PPT10u.0Mt+D=' = @B +  B(  r  S r5   r  S [w!    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