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Physicians response to patient reports of adverse drug effects. Drug Safety 2007)¡ ´Nfª,I DocumentSummaryInformation8ÿÿÿÿÿÿÿÿÿÿÿÿD Current Userÿÿÿÿÿÿÿÿÿÿÿÿ&DÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿYóº7Ÿ¨ Related WorkŸ¨�Automated 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 signal¡´B2…@/B  …@/ $$ª>c Œoó»8Ÿ¨ Related WorkŸ¨¿Pharmacoepidemiology databases used to confirm suspicions General practice research database (GPRD) (Wood & Martinez 2004) New Zealand Intensive Medicines Monitoring (IMMP) (Coulter 1998) Medicine Monitoring Unit (MEMO) (Evans et al. 2001) EHR databases used to find signals (Brown JS et al. 2007; Berlowitz DR et al. 2006; Wang X et al. 2009) Mainly coded data used Has potential for active real time surveillance Should reduce biased reporting¡Ê;Z¶ZZhZfZ;*3 !# E$$((,,O00ª$ ŠóäJŸ¨ Related WorkŸ Consortiums 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  ª‚ ,*! òóü íß4Qòóý íßg“ó·4Ÿ¨'Exploiting the Electronic Health Recordó¶3Ÿ¨"The Electronic Health Record (EHR)Ÿ¨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   ó¼:Ÿ¨"Research Opportunities: NLP IssuesŸ¨ÿOccurrence 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 ¡ê2P<PP‰PPPEPP;P\PPPPP2<‰  ÿÿfþ  ÿÿ™þ$$((ÿÿ™þ,,00ÿÿ™þ44ÿÿ™þ;88 <<ÿÿfþÿÿfþ)  ÿÿ™þÿÿfþªPd: %/ó¿;Ÿ¨*Research Opportunities: Statistical IssuesŸ äFind associations between drug, symptoms, and diseases Not explicit in EHR Large volumes of data Statistical significance vs. clinical significance Statistical associations  not relationships Drug treats condition / Drug causes condition Integrating time sequences is important For treats: condition must precede drug event For causes: drug event must precede condition¡7@àÿ@àÿ3-.(\73 -ÿÿþ  ÿÿþ $$(((,,00ÿÿfþ(4488ÿÿfþ$<<óÌ>Ÿ¨*Research Opportunities: Statistical IssuesŸ¨Confounding (indirect associations) Metolazone treats heart failure (HF) HF is manifested by shortness of breath (SOB) Metolazone and SOB indirectly related Higher order associations Drug interactions: Drug1, drug2, condition Drug-contraindications: Drug, disease, condition Rare ADEs¡$ZzZZ\Z Z$   ÿÿþ ÿÿþ   $$((,,004488çÿ<<çÿ= ª6$ H ˜óÀ<Ÿ¨4Other Research Opportunities: Knowledge Acquisition¡55Ÿ |Structured Knowledge bases UMLS relations (may_be_treated_by) Proprietary ones  usually unavailable Text/Semi-Structured Knowledge (need NLP) Spontaneous reporting databases: indications, drugs, adverse events Literature (Medline) Web sites (WebMD, Micromedix) Online medical textbooks Claims Data (Health IT payors)¡fK*¯ÿÿfþ* *¯ª>+¿ 2ó_ Ÿ¨%Text Mining for Knowledge Acquisition¡&&fÿÿfþª% Ÿ¨[Statistical methods: co-occurrences Discovered associations between diseases and diets from literature (Weeber M 2002) Identified disease candidate genes ( Hristovski D 2005) NLP systems Trends in medications based on the literature and narrative clinical reports (Chen ES 2007, 2008) Semantic relations in the literature (Hristovski D 2006) ¡À%� �%D &  N $$%((,,00ª>i- Ÿ  ó½9Ÿ¨6Overview of Our NLP-EHR based Pharmacovigilance SystemªóÎ?Ÿ¨"Natural Language Processing of EHRŸª óÊ=óÒAŸ¨Coded Output from NLPŸ žmed: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 item¡0ÐPuGª˜J? }  óÚEŸ¨ Coding IssuesŸ 6Not 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, & ¡À+$#[ÿÿfþ)  ÿÿfþ$ÿÿfþ#[ÿÿfþ  ÿÿfþóÐ@Ÿ¨Standardizing Coded DataŸª óÔBŸ¨>Standardizing Coded EHR Data: Laboratory Tests and Medications¡??Ÿ 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 àð rosaglitazone) Handling of combination medications 1.5% Lidocaine with 1:200,000 Epinephrine Handling of dose & Route Diazepam 2 MG Oral Tablet ¡)oES*)oE  ÿÿfþ†ÿÿfþÿÿfþ%*  ÿÿfþ$$((ÿÿfþ,,ÿÿfþ00ª„Ý   + 4  óÖCŸ¨Selecting and FilteringŸª óØDŸ¨Selecting and FilteringŸ¨“Dependence on accuracy of semantic classification UMLS classification errors - Finding: birth history, cardiac output, divorce + Finding: cardiomegaly, fever Temporal information difficult to obtain An adverse drug event should only follow drug event Processing of explicit time information is complex and vague Yesterday, last admission, 2/5 Information typically occur in reports without dates ¡î2U)q520  "ÿÿfþ)qÿÿfþ4  $$ÿÿfþ((ÿÿfþª, ûóÜFŸ¨Detect AssociationsóÝGŸ¨Detect AssociationsŸ¨ICorrect 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 ¡Ì&Z}ZDZZ Z+ZZ&}D ÿÿfþÿÿfþÿÿfþ +$$((ªëNó�"ó±1ó®0óÞHŸ¨Reduce ConfoundingóßIŸ¨Reduce ConfoundingŸ¨èCollect knowledge from external sources and associations Drug-treat-disease Disease-manifested by-symptom Drug-interacts with-drug Use Information theory Mutual Information (MI) Data processing inequality MI3 < (MI1, MI3) ¡n9ZKZZ3ZZZ9ÿÿfþ  ÿÿfþ  $$ÿÿfþ((,,0044ÿÿfþ88<<3çÿ çÿçÿ  çÿ$$((óèLŸ¨Initial Study: MethodsŸ¨É6 drugs chosen Ibuprofen, Morphine, Warfarin: longtime on market with known ADEs Bupropion, Paroxetine, Rosiglitazone: ADEs discovered after 2004 1 drug class: ACE inhibitors 25,074 textual discharge summaries in 2004 from NYPH processed using MedLEE NLP Reference standard created using expert knowledge sources Drug-potential ADE pairs determined Recall/precision calculated Qualitative analysis performed to classify drug-potential ADE pairs detected ¡®Z¡ZZb$_ b bGb9 b �$$ªú             3  = 9 �óêMŸ¨Initial Study: ResultsŸ¨ÑQuantitative 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% ¡ž /t’  /  ÿÿfþ P ªb góíNŸª Ÿª óhŸ¨"Study 2: Reduction of Confounding ¡##Ÿ¨¢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  Rª> eó¦.Ÿ¨Results ¡* f$ÿÿfþŸ¨PPrecision 0.86 when handling confounding 0.31 when without handling confounding¡. F `F`ªP óqŸ¨+Discussion: Limitations & Future Directions¡,,dÿÿfþŸ¨fMutual information only strategy to handle confounding More complex MI strategy will be explored Other statistical/knowledge based methods will be explored Inpatient data only/sicker patient population The same methods could be used for outpatient data as well - possibly more noisy Drug dosage, drug-drug and more complex interactions should be explored ¡‚7g.QI7g.Q  Iªt)�IóïOŸ¨+Discussion: Limitations & Future Directions¡,,dÿÿfþª+Ÿ¨®Small evaluation data set More comprehensive evaluation Limitations inherent from NLP, coding, association detection Limitations due to fragmented/incomplete patient data ¡ŒZZZvZ= 5` ª.u6 órŸ¨Summary¡f$ÿÿfþŸ¨iNeed 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 medicine¡N*4O½*4O½ ª,@ó¬/Ÿ¨Acknowledgement¡ÿÿfþŸ¨ 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((ªd1   3  0óç/ðDóù ó„óa§ói«ót±óu²ó‘½ó§Éó¯Êó³ÌóµÏó¾ÐóÁÑóÂÒóÃÓóÄÔóÅÕóÆÖóÇ×óÈØóÉÙóËÚóÍÛóÏÜóÑÝóÓÞóÕßó×àóÙáóÛâóàãóáäóâåóãæóåçóçèóééóëêóðëêøÏ ï (À`ð ÿÿÿÿÿÿÿ™ÿÿÿ–––`ð ÿÿÿ€€€Ì™33ÌÌÌÿ²²²`ð ÿÿÿ333ÝÝÝ€€€MMMêêê`ð ÿÿÌff3€€3™3€3ÌÿÌf`ð ÿÿÿ€€€ÿÌfÿÌÌÀÀÀ`ð ÿÿÿ€€€ÀÀÀfÿÿ™`ð ÿÿÿ€€€3™ÿ™ÿÌÌ̲²²£>ÿý?" dd@ÿÿïÿÿÿÿÿÿ ÿÿþ£~ÿý?" ddØ@ÿÿïÿÿÿÿÿÿ€ Ô €" Ð@€ ð`€»€ £nÿý?" dd@ÿÿïÿÿÿÿÿÿ   @@``€€P£R    @ ` €`£ p£>€£> fð^ððÜð( ð ððÒ ð “ ð6€@÷‡�ƒ¿Àÿ ðEƒ£¸ðà  ðTŸ¨ Click to edit Master title style¢!ª !ð ð ƒ ð0€Ð÷�ƒ¿Àÿ ð ·×�ðà  ðžŸ¨RClick to edit Master text styles Second level Third level Fourth level Fifth level¢!    ª SðÒ ð  Ó ðX¿ û?�ÿf¿ ÿ†††?¿ÿ€Ã ¿Base“"ñ6@¿ ÿÀ¿††N¿NÿN?NðpÀÀp ð Á ûðf² ð  C ð0€€A Ádbmi_logo_1"ñ¿ðÃVoðj² ð c ð4€€AÁW \cu_logo"ñ¿ð�Vðò ð ƒ ð0€ÀSJ�ƒ¿Àÿ "ñ¿ð^_Šðà   ðlŸ (*July 21 - 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