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NetBioSIG2012 annabauermehren

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Mining of electronic health records (EHRs) has recently gained importance. However, most efforts are restricted to analyzing drugs, diseases and their associations. In biomedical research, network analysis has provided the conceptual framework to interpret protein-protein interactions or gene-disease association networks via large-scale network maps.
We analyze associations between drugs, diseases, devices and procedures mined from EHRs using network analysis to extract hidden “modules of care” for hypothesis generation. In particular, we annotated the textual notes of the EHRs of one million patients in the Stanford Clinical Data Warehouse with disease, drug, procedure and device terms using ontologies such as SNOMED-CT or RxNorm. We then used standard co-occurrence statistics to establish associations between these clinical concepts and to construct networks. Hidden modules of care - clusters of diseases, drugs, procedures, devices – useful for hypothesis generation are extracted through network analysis approaches and visualized using Cytoscape.
We present a study for comparative effectiveness of Cilostazol vs. a control group in peripheral artery disease (PAD) patients (see Figure 1) and compare our results derived from the network analysis against standard methods such as regression analysis. We believe that network analysis allows us to uncover hidden (“latent”) modules of care not detected through standard approaches, which do not account for the connectivity of the clinical events and entities.

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NetBioSIG2012 annabauermehren

  1. 1. Network(analysis(of(unstructured( EHR(data(for(compara8ve( effec8veness(research( Anna$Bauer)Mehren$ ShahLab,$Stanford$Center$for$Biomedical$Informa:cs$
  2. 2. Background(>(PAD(•  Peripheral$artery$disease$(PAD):$obstruc:on$of$infra)renal$ abdominal$aorta$and$lower$extremity$arteries$$•  Symptoms:$IntermiEent$claudica:on$$•  Risk$factors:$Smoking,$Diabetes,$Obesity,$Hypertension,$Age$•  Treatments:$Lifestyle$changes,$Surgical$and$endovascular$ interven:ons,$Pharmacotherapy$$!$Cilostazol$7/17/12 NetBio SIG, 2012 2
  3. 3. Background(>(Cilostazol(•  Reversible$selec:ve$inhibitor$of$phosphodiesterase$(PDE)$type$III$•  Long)term$oral$milrinone$therapy$associated$with$life) threatening$cardiovascular$events$in$conges:ve$heart$failure$ (CHF)$pa:ents$$$$$$$Black$box$warning:$$$$ Cilostazol is contraindicated in patients with CHF$$$$$$Hypothesis:$ Cilostazol is not associated with increased risk of major adverse cardiovascular events (MACE)7/17/12 NetBio SIG, 2012 3
  4. 4. STRIDE( NCBO( •  1.6$million$pa:ents$ •  We$create$and$maintain$a$ library$of$more$than$300$ •  15$million$visits$ biomedical$ontologies$ •  25$million$coded$ICD9$ •  We$build$tools$and$web$ diagnoses$ services$to$enable$the$use$ of$ontologies$ •  9.5$million$clinical$free$ text$notes$ •  We$use$ontologies$for$ •  pathology$ annota:ng$EHRs$to$allow$ •  radiology$ clinically$relevant$studies$ •  transcrip:on$reports$7/17/12 NetBio SIG, 2012 4
  5. 5. Networks(for(compara8ve(effec8veness( •  Networks$have$been$successfully$applied$in$biology$ •  Can$we$use$networks$for$clinical$studies?$ •  We$want$to$use$networks$for$ •  Cohort$building$ Roque et al, PLoS Comput Biol. 2011; 7(8): e1002141. •  Analysis$of$clinical$outcome$ $7/17/12 NetBioSIG 2012 5
  6. 6. From(clinical(notes(to(pa8ent(feature(matrix( BioPortal – knowledge graph Text clinical note Creating clean lexicons Drugs Diseases Annotation Workflow Term$–$1$ :$ Term recognition tool NegEx :$ NCBO Annotator Patterns Term$–$n$ Devices Procedures Terms Recognized Patient feature matrix •  Negation detectionFurther$Analysis$ Select cohort of •  FH detection Interest Negation, FH detected 7/17/12 NetBio SIG, 2012 6
  7. 7. Dimension(reduc8on(using(ontologies(7/17/12 NetBio SIG, 2012 7
  8. 8. Cohort(building(–(restrict(by(follow(up(8me( Follow up time in peripheral artery disease patients 3000 Patient timeline PAD Last note 2500 tPAD tlast t 2000 Follow up time Frequency 1500 1000 5757 PAD patients 500 0 0 365 1000 2000 3000 4000 5000 6000 follow up time in 30 day intervals7/17/12 NetBio SIG, 2012 8
  9. 9. Cohort(building(–(set(8me( Patient timeline PAD CIL Last noteCilostazol tpatient t PAD t CIL= t0 t last Matching Outcome Median = 22 days PAD Last noteOther PAD tpatient t PAD t0 t last 22 days before after7/17/12 NetBio SIG, 2012 9
  10. 10. Matching( Pa8ent>pa8ent(similarity(network( Propensity>score(matching( 1159( 1.  Choose$variables$for$matching$ Pa:ents$ 5776( A∩B J(A, B) = 1− A∪B Nearest(neighbor( Pa:ents$ 5776( Matching((1:1)( 0 0.6 0.8 0.6 0.5 0.8 2.  Compute$PS$based$on$variables$(logis:c$Cilostazol( 0 0.8 0 0.9 0.7 0.8 0.9 0.3 0.9 regression)$ Pa:ents$ 0 0.7 0.8 3.  Nearest$neighbor$matching$(1:1)$ 0 0.8 0 5776( Control( Concepts$ Concepts$ 1 0 1 0 0 1 17( Pa:ents$ 1 0 1 0 0 1 1159( 0 0 1 1 1 0 1 1 0 0 0 1 Pa:ents$ 0 0 1 1 1 0 1 0 1 0 0 1 1 1 0 0 0 1 0 0 1 1 1 1 1 0 1 0 0 1 0 0 1 0 0 1 0 0 1 1 1 1 446( 0 0 1 0 0 1 446( 7/17/12 NetBio SIG, 2012 10
  11. 11. Matching(>(comparison(! Variable Before Matching Patient-patient similarity Propensity score ! network matching ! Treatment Control p-value Control p-value Control p-value ! Demographics (n= 223) (n= 5534) (n= 223) (n= 223) ! Age (at indication onset), mean (sd) 71.22 70.43 0.295 72.05 0.41196 70.87 0.74704 (11.02) (12.46) (10.62) (11.51) Gender (female), n (%) 37.22 45.94 0.0090723 36.65 0.84432 35.87 0.76777 Race , (%) Asian 8.52 7.41 0.56047 6.33 0.36671 10.31 0.50525 Black 2.69 3.71 0.36423 3.61 0.588 0.90 0.15684 Unknown 22.87 26.17 0.25365 22.17 0.82063 20.63 0.57404 White 65.47 62.22 0.31854 67.87 0.54642 67.27 0.68645 Comorbidities Coronary artery disease, n (%) 5.38 6.47 0.48345 4.98 0.83089 6.28 0.69516 Congestive heart failure, n (%) 25.56 22.84 0.36255 20.36 0.21361 30.49 0.36255 Hypertension, n (%) 10.76 11.31 0.79597 9.50 0.75135 10.31 0.87893 Co-prescriptions Beta blocking agents, n (%) 75.34 60.77 1.6611e-06 69.68 0.20252 74.89 0.90693 ACE inhibitors, plain, n (%) 78.03 69.57 0.0032697 67.87 0.013595 78.92 0.81386 Platelet aggregation inhibitors excl. 91.93 79.00 8.1983e-11 89.59 0.41347 95.51 0.072929 heparin, n (%) Vasodilators, n (%) 32.29 26.36 0.064893 31.67 0.83902 37.22 0.28753 History of Cardiac arrhythmia, n (%) 32.29 32.17 0.96957 23.08 0.03383 33.18 0.84006 Stroke, n (%) 17.94 18.31 0.88877 15.84 0.61129 21.52 0.33903 Myocardial infarction, n (%) 17.94 15.87 0.43015 13.58 0.23919 19.73 0.63765 Vascular surgical procedures, n (%) 74.44 47.71 < 2.22e-16 65.61 0.048937 74.44 1 Bypass surgery, n (%) 41.70 26.56 1.0506e-05 36.20 0.24269 40.36 0.75073 7/17/12 NetBio SIG, 2012 13
  12. 12. Cohort(building(–(set(8me( Patient timeline PAD CIL Last noteCilostazol tpatient t PAD t CIL= t0 t last Matching Outcome Median = 22 days PAD Last noteOther PAD tpatient t PAD t0 t last 22 days before after7/17/12 NetBio SIG, 2012 14
  13. 13. Outcome(comparison( Concept>concept(network( Dispropor8onality(analysis($ $$ $ &β β β β # $ 10 11 13 1d $ ! $β 21 β 20 β 23 β ! 2d $β β β β ! 31 32 30 3d $ ! $ ! $ ! $ $β ! % β β β ! " Compute edges d1 d2 d3 d0 cofreqcid1,cid 2 ascid1,cid 2 = log( freq1cid1 * freq2 cid 2 ) cilostazol n - 0.5 2.5 4 10 Logistic regression - 0.5 2.5 4 10 - 1.3 2 0 Odds ratios − cilostazol vs. control - 1.3 2 0 - 0 0 1 0 0 1 1 Atrial fibrillation ● similarity ● - 0 0 psm 0 1 1 0 1 - 1 Bypass surgery ● - 1 0 1 0 0 1 ● cephalexin cane - Cardiac arrythmia ● 0 1 1 0 0 ● - ultrasound Coronary stents ● doppler imaging 1 0 1 0 0 control ultrasonography ● amoxicillin doppler studies 1 1 1 1 0 Death ● angioplasty atherectomy ● revascularization wheelchair bypass graft Electric countershock ● vascular cilostazol ● surgical procedures diagnostic hydralazine congestive heart imaging Myocardial infarction ● pneumonia surgical revision failure ● heart failure bypass Stroke ● nifedipine testosterone ● amiodarone pravastatin vascular diseases carotid Vasulcar surgical procedures ● pantoprazole insulin glargineendarterectomy ● obesity transplantation ramipril fentanyl Ventricular fibrillation ● zolpidem trimethoprim ● decompressive incision Ventricular tachicardia ● coronary sulfamethoxazole diazepam angiography ● fluoroscopic heart angiography transplantation tacrolimus temazepam 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 7/17/12 NetBio SIG, 2012 15
  14. 14. Concept>concept(network( cephalexin cane doppler ultrasound ultrasonography imaging amoxicillin doppler studies angioplasty atherectomy wheelchair Vascular surgical procedures revascularization bypass graft vascular cilostazol surgical procedures diagnostic hydralazine congestive heart imaging pneumonia surgical revision failure Heart failure bypass heart failure nifedipine testosterone amiodarone pravastatin vascular diseases carotid pantoprazole insulin glargineendarterectomy obesity transplantation ramipril fentanyl zolpidem trimethoprim decompressive Heart incision coronary sulfamethoxazole diazepam angiography transplantation fluoroscopic heart angiography transplantation tacrolimus temazepam7/17/12 NetBio SIG, 2012 16
  15. 15. Dispropor8onality(analysis( Odds ratios − cilostazol vs. control Atrial fibrillation ● similarity ● psm Bypass surgery ● ● Cardiac arrythmia ● ● Coronary stents ● ● Death ● ● Electric countershock ● ● Myocardial infarction ● ● Stroke ● ● Vasulcar surgical procedures ● ● Ventricular fibrillation ● ● Ventricular tachicardia ● ● 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.57/17/12 NetBio SIG, 2012 17
  16. 16. Conclusions(•  Technical$ •  Pa:ent)pa:ent$network$based$on$similarity$ in$annota:ons$can$be$used$for$cohort$ building$ cephalexin cane •  Concept)concept$network$based$on$co) doppler ultrasound ultrasonography imaging amoxicillin doppler studies angioplasty atherectomy revascularization wheelchair occurrence$in$clinical$notes$can$be$used$for$ bypass graft vascular cilostazol surgical procedures diagnostic hydralazine congestive heart imaging pneumonia surgical revision failure bypass heart failure nifedipine analyzing$clinical$outcome$ testosterone amiodarone pravastatin vascular diseases carotid pantoprazole insulin glargineendarterectomy obesity transplantation ramipril fentanyl zolpidem trimethoprim decompressive incision coronary sulfamethoxazole diazepam angiography fluoroscopic heart angiography transplantation tacrolimus temazepam•  Medical$ Cilostazol is contraindicated in patients with CHF •  No$significant$differences$in$MACE$ comparing$cilostazol$vs.$control$$ Cilostazol is not associated with increased risk of major adverse cardiovascular events (MACE) $7/17/12 NetBio SIG, 2012 18
  17. 17. Future(work( angioplasty wheelchair cilostazol•  Technical$ pneumonia hydralazine congestive heart failure heart failure heart failure •  Improve$aggrega:on$of$concepts$ amiodarone pravastatin carotid pantoprazole insulin glargineendarterectomy •  Might$improve$cohort$building$ obesity transplantation zolpidem trimethoprim •  Useful$for$outcome$analysis$based$on$networks$ coronary angiography sulfamethoxazole•  Medical$ •  Repeat$study$in$different$hospital$ •  Profile$PAD$pa:ents$using$all$annota:ons$using$concept) concept$networks$for$hypothesis$genera:on$7/17/12 NetBio SIG, 2012 19
  18. 18. Acknowledgements(•  ShahLab$ •  Nigam$Shah$ •  Paea$LePendu$ •  NCBO$Team$ •  Rave$Harpaz$ •  Mark$Musen$ •  Srinivasan$Iyer$ •  NIH$funding$ •  Amogh$Vasekar$ $ •  Kenneth$Jung$ •  STRIDE$Team$ •  Tanya$Podchiyska$•  Medical$collaborator$ •  Todd$Ferris$ •  Nicholas$Leeper$ $ •  John$Cooke$7/17/12 NetBio SIG, 2012 20

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