Clinical Research Informatics: From Bedside to Silicon and Back Laura K. Wiley Division of Biomedical Informatics and Personalized Medicine Dept of Biostatistics and Informatics @GenomeGal

So what is Clinical Research Informatics?

What’s in an EHR?

How can we leverage EHRs? Clinical Trial Recruitment Analytics/ Learning Healthcare System EHR Repository Population Health/ Epidemiology Link to Biobank for Genetic Research

Coming Soon to a University Near You!

I’m doing a study on diabetes… Compass can you get me a list of all the diabetics?

How Do We Find Phenotypes? Natural Language Processing/ Keywords Billing codes True cases Laboratory Measurements Medications

How Do We Find Phenotypes? Definite Cases (algorithm-defined) Possible Cases (require manual review) Excluded (algorithm-defined) Controls (algorithm-defined)

A More Complex Example – Drug Adverse Reactions Statins – Widely used ~1/4 Americans > 45 circa 2010 Myotoxicity side-effect leading cause of discontinuation

Goal Test a variety of phenotyping algorithms against a single, consistent definition of statin myotoxicity. “Any muscle symptom attributed to statin by care provider anywhere in the patient’s medical record.” Wiley, et. al. AMIA Jt Summits Transl Sci Proc. 2015

Methods – ICD9 & CK Algorithms ICD-9 Codes Alone Drug Side Effect (5, e.g., 972.2 – poisoning by antilipemic & antiarteriosclerotic drugs) General Muscle Effects (7, e.g., 359.9 – myopathy unspecified) Creatine Kinase (CK) – after 1st Statin CK > 3x Upper Limit Normal (ULN) CK (any value), not at same time as troponin CK > 3x ULN, not at same time as troponin CK (any value), only measurement in 5 days CK > 3x ULN, only measurement in 5 days Wiley, et. al. AMIA Jt Summits Transl Sci Proc. 2015

Methods – Allergy Algorithms Listed Drug Allergies Problem List HISTORY OF PRESENT ILLNESS: Mr. XXX is a pleasant 50 year old gentleman with a history of diabetes mellitus and hyperlipidemia who presents with unspecified muscle pains, possibly due to his statin. ALLERGIES: Statins unkown; Atorvastatin causes myopathy MEDICATIONS: Metformin, Niacin, Pitavastatin History & Physical Adverse & Allergic Drug Reactions Atorvastatin (unknown) Simvastatin (LFTs) Medications Metformin ER 500 mg Pitavastatin 4mg Niacin 250mg Health Problems Diabetes Mellitus Hyperlipidemia All Code Available at: https://github.com/laurakwiley/StatinMyopathy Wiley, et. al. AMIA Jt Summits Transl Sci Proc. 2015

Methods – Keyword Algorithms Keyword Searching Clinical Comm. History & Physical **NAME[STARUSER]: Mr. XXX called saying that he is having severe muscle pain after increasing his dose of atorvastatin and would to know what to do. **NAME[STARUSER]: Please call him back and tell his to stop taking the statin for 2 wks and see if his symptoms resolve. **NAME[STARUSER]: Done. **NAME[STARUSER]: Mr. XXX called saying that he is having severe muscle pain after increasing his dose of atorvastatin and would to know what to do. **NAME[STARUSER]: Please call him back and tell his to stop taking the statin for 2 wks and see if his symptoms resolve. **NAME[STARUSER]: Done. **NAME[STARUSER]: Mr. XXX called saying that he is having severe muscle pain after increasing his dose of atorvastatin and would to know what to do. **NAME[STARUSER]: Please call him back and tell his to stop taking the statin for 2 wks and see if his symptoms resolve. **NAME[STARUSER]: Done. HISTORY OF PRESENT ILLNESS: Mr. XXX is a pleasant 50 year old gentleman with a history of diabetes mellitus and hyperlipidemia who presents with unspecified muscle pains, possibly due to his statin. ALLERGIES: Statins unkown; Atorvastatin causes myopathy MEDICATIONS: Metformin, Niacin, Pitavastatin HISTORY OF PRESENT ILLNESS: Mr. XXX is a pleasant 50 year old gentleman with a history of diabetes mellitus and hyperlipidemia who presents with unspecified muscle pains, possibly due to his statin. ALLERGIES: Statins unkown; Atorvastatin causes myopathy MEDICATIONS: Metformin, Niacin, Pitavastatin HISTORY OF PRESENT ILLNESS: Mr. XXX is a pleasant 50 year old gentleman with a history of diabetes mellitus and hyperlipidemia who presents with unspecified muscle pains, possibly due to his statin. ALLERGIES: Statins unkown; Atorvastatin causes myopathy MEDICATIONS: Metformin, Niacin, Pitavastatin 2.64, 5.33 0.5, 2.64 All Code Available at: https://github.com/laurakwiley/StatinMyopathy Wiley, et. al. AMIA Jt Summits Transl Sci Proc. 2015

Results – Algorithms Performance ICD-9 Codes CK Elevation Allergies Keywords Combined Allergy+Keyword Allergy+Keyword+ ICD-9 Allergy+Keyword+ ICD-9 + CK (any value) no troponin ICD-9 (PPV/Precision ~ 0.7; NPV ~0.7) Sensitivity/Recall: 0.48 Specificity: 0.86 PPV = 0.7 NPV = 0.7 Creatine Kinase (PPV ~ 0.5-0.65; NPV ~0.6-0.83) CK >500, single measurement Sensitivity: 0.07 Specificity: 0.97 CK (any), single measurement; CK>500, any or no troponin Sensitivity: 0.3-0.32 Specificity: 0.81-0.89 CK (any) no troponin Sensitivity: 0.89 Specificity: 0.35 Allergy – Combined (PPV ~88->97%; NPV ~79%) Sensitivity: 0.64 -> 0.63 Specificity: 0.94 -> 0.99 Keyword – Combined (PPV ~78-85%; NPV ~85->87%) Sensitivity: 0.78 -> 0.81 Specificity: 0.85 -> 0.90 Combined Text Only (PPV ~ 86%; identified 109 of the 123 cases) Sensitivity: 0.88 Specificity: 0.90 Combined Text & ICD9 (PPV ~ 81%; identified 116 of the 123 cases) Sensitivity: 0.94 Specificity: 0.84 Combined All (PPV ~ 51%; identified 122 of the 123 cases) Sensitivity: 0.99 Specificity: 0.32 Wiley, et. al. AMIA Jt Summits Transl Sci Proc. 2015

What’s Your Application? Clinical Trial Recruitment Analytics/ Learning Healthcare System EHR Repository Population Health/ Epidemiology Link to Biobank for Genetic Research

Some General thoughts…. Detected truth Who the algorithm detects as having a rxn Case/Control Algorithm Approach & Implementation Recorded Truth If / How medical record contains reaction Manual Review Patient – Provider Conversation Absolute TRUTH Statin causes myotoxicity for Patient Can’t Capture

Practical Clinical Research Informatics Acknowledgements Josh Denny Jeremy Moretz Josh Peterson William Bush Want to learn more? BSBT6310/BIOS6310 – Practical Clinical Research Informatics M. Kahn and L. Wiley Spring 2019 Funding Integrated, Individualized and Intelligent Prescribing (I3P) – U01HG007253 Informatics Tools for Pharmacogenomic Discovery Using Practice-Based Data (iPGx) – R01GM103859 VGER, The Vanderbilt Genome-Electronic Records Project – U01HG008672 Genetics Training Grant - T32GM080178 NLM Training Grant – T15LM007450 BioVU: Vanderbilt CTSA - UL1 TR000445 Instrumentation Award - 1S10RR025141-01 Institutional Funding; RC2GM092618; U01HG004603