Assessment of Patient Medication Adherence, Medical Record Accuracy, and Medication Blood Concentrations for Prescription and Over-The-Counter Medications

Home , Chlorpropamide, Dofetilide, Domperidone, Eslicarbazepine acetate, Glipizide, Hyoscyamine

Supplementary Online Content

Sutherland JJ, Morrison RD, McNaughton CD, et al. Assessment of patient medication adherence, medical record accuracy, and medication blood concentrations for prescription and over-the-counter medications. JAMA Netw Open. 2018;1(7):e184196. doi:10.1001/jamanetworkopen.2018.4196

eMethods eTable 1. Multiplex Assay Panel Medications eTable 2. Multiplex Assay Panel Medications, Medication Classes, Limits of Detection, Reference Ranges and Biological Half Life eTable 3. Proportion of Samples With Detected Medication, by Medication Category eTable 4. Proportion of Medication Detections Without Evidence of Prescription, by Medication Category eFigure 1. Medication Detection Rate in Two Cohorts eFigure 2. Comparison of Differential Prescription and Detection Rates in ED vs Residuals Cohorts eFigure 3. Adherence to Prescription Drugs eFigure 4. Comparison of Naïve Estimates of Adherence by Medication Class vs. Coefficients From Logistic Regression Modelling eFigure 5. Comparison of Detection Rates for Medications not Listed in Subjects’ Health Record in Two Cohorts

This supplementary material has been provided by the authors to give readers additional information about their work.

eMethods

Sample collection

Samples were collected in serum phlebotomy tubes and processed within four hours of collection. Resulting serum was frozen at -70°C until shipment on dry ice to Precera Biosciences for analysis. The key linking study-specific identifiers to EHR information was maintained by study personnel at the site and not shared with laboratory or analysis personnel. Laboratory personnel were blinded to study participants’ records, including the EHR medication list, during the measurement phase of the study.

LC/MS/MS analysis

Sample analysis was executed under the guidelines set forth by the CAP and standard operating procedures commensurate with CLIA-registered operations. Samples were thawed, mixed, and transferred to 96-well plates for processing. Internal standard working solution was added and protein precipitation was performed using Phenomenex Impact Protein Precipitation Plates. Eluate was transferred to a new plate and dried under Nitrogen prior to reconstitution for LC/MS/MS analysis. Reconstituted samples were processed using a Shimadzu Nexera X2 liquid chromatography system (Columbia, MD) fitted with a Phenomenex 2.1 x 50 mm, 1.7um C18 column (Torrence, CA). Sample analysis was performed on a Sciex 5500 Q-Trap Mass Spectrometer (Framingham, MA) with TurboV ion source. Data collection was performed with Sciex Analyst software, version 1.6.2, and data analysis was performed using Indigo BioAutomation Ascent software (Indianapolis, IN).

Optimal grade methanol and acetonitrile were obtained from Fisher Scientific (Waltham, MA). Formic acid, ammonium acetate, ammonium formate, and water were LC/MS grade and obtained from Sigma-Aldrich (St. Louis, MO). Dimethylsulfoxide was obtained from Sigma-Aldrich. Ammonium hydroxide was obtained from Thermo Fisher Scientific. Drug naïve human serum used in validation studies was obtained from Bioreclamation IVT (Westbury, NY). All analytical standards were obtained at the highest purity available. Stock solutions were prepared individually in DMSO, water, methanol, or acetonitrile, then combined. Standard Curve and Quality Control samples were prepared in drug naïve human serum. Assay linearity, precision, accuracy, and detection were assessed by adding various amounts of each test drug to human serum. Each of the analytes assayed passed strict analytical validation criteria. The final test panel detected the presence of 277 unique analytes, corresponding to 263 parent drugs (eTable 2).

Quantitative Medication Reporting

After measurement, medication lists were compared to LC/MS/MS data. The primary information source was the AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry1, which provides evidence-based reference ranges for 128 marketed psychiatric medications. If a medication was not listed in this primary source, secondary sources derived from primary literature were utilized as cited. Finally, if no literature values could be obtained, drug label information was utilized.

Annotation of drugs by class Medications were mapped to drug classes according to the National Health and Nutrition Examination Survey (NHANES) resource (https://wwwn.cdc.gov/nchs/nhanes/1999-2000/RXQ_DRUG.htm accessed 11/20/2017). Medications were grouped using the variables RXDDCN1A and RXDDCN1B. Groupings were adjusted manually to achieve ≥20 prescriptions and/or detections per category. The categories of medications as used throughout this work are provided in eTable 2 (column: medication class).

Coverage of US medication prescribing The most recent NHANES prescription drug survey for 2013-2014 (https://wwwn.cdc.gov/Nchs/Nhanes/2013- 2014/RXQ_RX_H.htm, accessed 03/26/2018) was used to evaluate coverage of the assay. Only 1870 subjects aged 20 years or older and reported to be using 3 or more medications were retained (i.e. a common definition of polypharmacy). Medications were classified as small molecule oral drugs using resources such as Wikipedia

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(https://www.wikipedia.org; accessed 03/26/2018) and DrugBank (https://www.drugbank.ca; accessed 03/26/2018). This definition excluded therapeutic antibodies, hormones, and vitamins/supplements (e.g. potassium chloride). Hormones are small molecules that can be detected via LC/MS/MS as employed herein, but their natural presence in the body reduces the utility of blood-based detection for medication management. Combination drugs (e.g. ACETAMINOPHEN; HYDROCODONE) were mapped to individual agents and treated as individual prescriptions. Each prescription was weighted according to the subject variable WINT2YR. The weighted sum for all prescriptions in polypharmacy adults was used to normalize each of 554 unique drugs, ranging from 4.9% (lisinopril, i.e. the most commonly reported medication and accounting for 4.9% of all oral drug prescriptions) to 0.002% (sofosbuvir, the least commonly reported medication).

Detection rate for prescribed drugs and drug classes The proportion of prescribed drugs detected in patient serum was calculated by excluding prescriptions with PRN status (i.e. prescribed for use “as-needed”). Unless indicated otherwise, when calculating the proportion of medications detected for a given drug, ≥ 20 prescriptions were required in order to avoid estimating detection proportions from very few prescriptions. Calculation of detection proportions in Figure 1 were obtained by pooling prescriptions from the three clinic sample cohorts and our previously described cohorts7,12. For those parent drugs with metabolites on the panel, we considered the prescribed drug ‘detected’ if parent and/or metabolites were detected.

Patient medication adherence (adherence drug subset) For evaluating a patient’s overall adherence to prescribed medications, we excluded medications that may be dosed infrequently or administered non-orally: methotrexate, budesonide, buprenorphine, clonidine, dexamethasone, diclofenac, fentanyl, ketorolac, and prednisolone. Further, we excluded 54 drugs with biological half-life ≤ 4 hours having low probability of detection (Figure 1) or prescribed fewer than 20 times across our pooled datasets and hence insufficiently prescribed to estimate detection rates. We also exclude drugs prescribed PRN (“as-needed”), as non-detection does not indicate non-adherence. The complete set of excluded drugs are denoted in eTable 2. In total, 189 drugs were used to calculate each patient’s overall adherence to prescribed medications, ranging from 0% to 100% adherence. In our analyses of factors affecting overall medication adherence, we focused on polypharmacy patients, defined as 3 or more prescribed non-PRN medications from the 189 drug subset.

Drug-drug interactions Elsevier Gold Standard database (https://www.elsevier.com/solutions/drug-database; accessed 03/22/2018) was used as the source of DDI information.

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eTable 1. Multiplex Assay Panel Medications

Medication category Drugs anti-infectives cephalexin, efavirenz, emtricitabine, hydroxychloroquine, itraconazole, ketoconazole, lamivudine, nitrofurantoin, oseltamivir, penicillin, sofosbuvir antineoplastics abiraterone, raloxifene angiotensin converting benazepril, enalapril, lisinopril, quinapril, ramipril enzyme inhibitors angiotensin II inhibitors candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan antiadrenergic agents, alfuzosin, doxazosin, prazosin, reserpine, tamsulosin, terazosin peripherally acting antiarrhythmic agents amiodarone, diltiazem, dofetilide, dronedarone, flecainide, fosphenytoin, phenytoin, procainamide, quinidine, verapamil beta-adrenergic acebutolol, atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, blocking agents nebivolol, pindolol, propranolol calcium channel amlodipine, felodipine, nifedipine blocking agents diuretics acetazolamide, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, torsemide, triamterene other cardiovascular cilostazol, clonidine, guanfacine, ranolazine agents anticonvulsants carbamazepine, divalproex, eslicarbazepine acetate, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, valproic acid, zonisamide benzodiazepines alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazepam, temazepam narcotic analgesics buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone non-benzodiazepine buspirone, butabarbital, eszopiclone, hydroxyzine, meprobamate, anxiolytics pentobarbital, phenobarbital, primidone, secobarbital, zaleplon, zolpidem Non-steroidal anti- acetaminophen, celecoxib, diclofenac, etodolac, fenoprofen, ibuprofen, inflammatory drugs indomethacin, ketoprofen, ketorolac, meclofenamate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin other central nervous armodafinil, atomoxetine, baclofen, carisoprodol, cyclobenzaprine, system agents agents dexmethylphenidate, diphenhydramine, domperidone, donepezil, eletriptan, meclizine, metaxalone, methocarbamol, methylphenidate, metoclopramide, modafinil, pramipexole, prochlorperazine, promethazine, rivastigmine, ropinirole, sumatriptan, tizanidine anticoagulants apixaban, dabigatran, rivaroxaban, warfarin antiplatelet agents clopidogrel, dipyridamole, hyoscyamine, pentoxifylline, ticagrelor, ticlopidine gastrointestinal agents cimetidine, dexlansoprazole, esomeprazole, famotidine, lansoprazole, omeprazole, pantoprazole, rabeprazole, ranitidine genitourinary tract darifenacin, mirabegron, oxybutynin, sildenafil, solifenacin, tadalafil, agents tolterodine, vardenafil hormones/hormone budesonide, dexamethasone, dutasteride, finasteride, prednisolone, modifiers prednisone antidiabetic agents alogliptin, canagliflozin, chlorpropamide, dapagliflozin, empagliflozin, glimepiride, glipizide, glyburide, linagliptin, metformin, nateglinide, pioglitazone, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolbutamide antigout agents colchicine, febuxostat, probenecid

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Medication category Drugs antihyperlipidemic atorvastatin, ezetimibe, fenofibrate, fenofibric acid, gemfibrozil, pravastatin, agents rosuvastatin, simvastatin miscellaneous agents apremilast, bupropion, dalfampridine, leflunomide, methotrexate, varenicline antidepressants amitriptyline, amoxapine, citalopram, clomipramine, desimipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, levomilnacipran, milnacipran, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, trazodone, trimipramine, venlafaxine, vilazodone, vortioxetine antipsychotics aripiprazole, clozapine, fluphenazine, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, quetiapine, risperidone, thioridazine, ziprasidone antihistamines cetirizine, chlorpheniramine, desloratadine, doxylamine, fexofenadine, levocetirizine, loratadine leukotriene modifiers montelukast other respiratory agents dextromethorphan, pseudoephedrine, roflumilast

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eTable 2. Multiplex Assay Panel Medications, Medication Classes, Limits of Detection, Reference Ranges and Biological Half Life

Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert itraconazole itraconazole No anti-infectives NA NA 400 2000 4000 30 Yes ketoconazole ketoconazole Yes anti-infectives 40 4000 1000 3000 6000 8 No, non-oral hydroxychloro- hydroxychloro- No anti-infectives NA NA NA 500 NA 1E3 Yes quine quine sofosbuvir sofosbuvir No anti-infectives NA NA NA NA NA NA NPD oseltamivir, oseltamivir Yes anti-infectives 2 500 NA NA NA 8 Yes oseltamivir acid efavirenz efavirenz Yes anti-infectives 20 5000 333 3000 6000 47.5 Yes emtricitabine emtricitabine Yes anti-infectives 2 2000 NA NA NA 10 Yes lamivudine lamivudine Yes anti-infectives 8 2000 NA NA NA 6 Yes No, short cephalexin cephalexin No anti-infectives NA NA 12000 30000 NA 1 half-life No, short penicillin penicillin No anti-infectives NA NA 100 2500 NA 0.5 half-life No, short nitrofurantoin nitrofurantoin Yes anti-infectives 20 5000 1000 3000 3000 1 half-life raloxifene raloxifene Yes antineoplastics 0.2 50 0.67 1.33 NA 32.5 Yes abiraterone abiraterone No antineoplastics NA NA 19.2 209 NA 12 Yes benazepril, angiotensin converting benazepril Yes 0.2 50 3 7 NA 10.5 Yes benazeprilat enzyme inhibitors enalapril, angiotensin converting enalapril Yes 2 500 10 50 300 9.5 Yes enalaprilat enzyme inhibitors angiotensin converting lisinopril lisinopril Yes 3 500 20 70 500 12 Yes enzyme inhibitors angiotensin converting No, short ramipril ramiprilat Yes 0.4 100 1 40 80 3 enzyme inhibitors half-life angiotensin converting No, short quinapril quinaprilat No NA NA NA NA NA 2 enzyme inhibitors half-life

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert candesartan candesartan Yes angiotensin II inhibitors 4 400 80 180 540 6 Yes irbesartan irbesartan Yes angiotensin II inhibitors 40 4000 1900 3300 6600 13 Yes losartan losartan Yes angiotensin II inhibitors 2 800 67 600 1800 2 Yes olmesartan olmesartan acid Yes angiotensin II inhibitors 4 1000 NA NA NA 13 Yes telmisartan telmisartan Yes angiotensin II inhibitors 2 500 6 225 NA 24 Yes valsartan valsartan Yes angiotensin II inhibitors 80 20000 800 6000 12000 7.5 Yes other cardiovascular No, often clonidine clonidine No NA NA 1 2 10 12.5 agents non-oral other cardiovascular guanfacine guanfacine Yes 0.2 50 NA NA NA 13.5 Yes agents antiadrenergic agents, alfuzosin alfuzosin Yes 0.4 100 3 60 120 6 Yes peripherally acting antiadrenergic agents, doxazosin doxazosin No NA NA 10 150 300 16 Yes peripherally acting antiadrenergic agents, No, short prazosin prazosin No NA NA 1 20 900 2.9 peripherally acting half-life antiadrenergic agents, reserpine reserpine No NA NA 1.5 3 NA 75 Yes peripherally acting antiadrenergic agents, tamsulosin tamsulosin Yes 0.4 100 2.86 21.74 NA 12 Yes peripherally acting antiadrenergic agents, terazosin terazosin Yes 5 500 20 80 160 10 Yes peripherally acting other cardiovascular ranolazine ranolazine Yes 5 5000 374 1083 NA 7.95 Yes agents flecainide flecainide Yes antiarrhythmic agents 1 400 400 800 1000 15 Yes phenytoin phenytoin No antiarrhythmic agents NA NA 10000 20000 25000 40 Yes No, short procainamide procainamide Yes antiarrhythmic agents 40 10000 4000 8000 10000 3.5 half-life quinidine quinidine Yes antiarrhythmic agents 1 1000 1000 5000 6000 8 Yes fosphenytoin phenytoin No antiarrhythmic agents NA NA NA NA NA NA NPD

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert amiodarone, N- amiodarone desethyl- Yes antiarrhythmic agents 100 5000 500 2000 3000 75 Yes amiodarone dofetilide dofetilide Yes antiarrhythmic agents 0.2 50 2 5.5 NA 9 Yes dronedarone dronedarone Yes antiarrhythmic agents 0.5 500 84 167 NA 24 Yes diltiazem diltiazem Yes antiarrhythmic agents 2 500 30 130 1000 4 Yes No, short verapamil verapamil Yes antiarrhythmic agents 4 1000 20 250 1000 4 half-life beta-adrenergic acebutolol acebutolol Yes 20 5000 200 2000 20000 7 NPD blocking agents beta-adrenergic atenolol atenolol No NA NA 100 1000 2000 9 Yes blocking agents beta-adrenergic bisoprolol bisoprolol Yes 2 500 10 100 200 11 Yes blocking agents metoprolol, beta-adrenergic metoprolol alpha-OH- Yes 1 1000 35 500 650 5 Yes blocking agents metoprolol beta-adrenergic nebivolol nebivolol Yes 1 100 6.7 60 120 10 Yes blocking agents beta-adrenergic carvedilol carvedilol Yes 2 500 20 150 300 8 Yes blocking agents beta-adrenergic labetalol labetalol Yes 10 1000 30 180 1000 6.5 Yes blocking agents beta-adrenergic nadolol nadolol Yes 8 2000 10 250 1300 22 Yes blocking agents beta-adrenergic No, short pindolol pindolol Yes 4 400 20 150 700 3.5 blocking agents half-life beta-adrenergic No, short propranolol propranolol Yes 1 1000 20 300 1000 4 blocking agents half-life calcium channel amlodipine amlodipine Yes 0.5 500 3 15 88 42 Yes blocking agents calcium channel felodipine felodipine No NA NA 1 12 10 24.5 Yes blocking agents

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert calcium channel nifedipine nifedipine Yes 0.8 200 25 150 150 3.5 Yes blocking agents No, short acetazolamide acetazolamide Yes diuretics 80 20000 10000 20000 30000 4 half-life No, short bumetanide bumetanide No diuretics NA NA 1 5 NA 1.25 half-life No, short furosemide furosemide Yes diuretics 120 30000 2300 25600 NA 2 half-life torsemide torsemide Yes diuretics 4 1000 64 521 NA 4.5 Yes triamterene triamterene Yes diuretics 2 500 10 100 200 3 Yes No, short chlorothiazide chlorothiazide Yes diuretics 80 20000 2000 18000 54000 1.5 half-life chlorthalidone chlorthalidone No diuretics NA NA 150 300 2000 46 Yes hydrochloro- hydrochloro- Yes diuretics 8 2000 40 2000 4000 11 Yes thiazide thiazide indapamide indapamide Yes diuretics 2 500 130 250 NA 14.5 Yes metolazone metolazone Yes diuretics 0.05 50 5.15 10.24 NA 11 Yes other cardiovascular cilostazol cilostazol Yes 4 1000 180 540 NA 12 Yes agents No, short eletriptan eletriptan Yes other CNS agents 0.4 100 NA NA NA 4 half-life No, short sumatriptan sumatriptan Yes other CNS agents 2 500 18 60 120 2 half-life celecoxib celecoxib Yes NSAIDs 50 2000 360 800 1600 13.5 Yes acetaminophen acetaminophen No NSAIDs NA NA 10000 20000 2E5 2 Yes No, often buprenorphine buprenorphine Yes narcotic analgesics 0.2 50 0.7 1.6 10 3.5 non-oral codeine, dihydrocodeine, No, short codeine hydrocodone, Yes narcotic analgesics 2 500 30 250 500 3.5 half-life morphine, norhydrocodone

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert No, short dihydrocodeine dihydrocodeine Yes narcotic analgesics 2 500 30 50 1000 3.5 half-life fentanyl fentanyl Yes narcotic analgesics 2 500 3 300 600 2.5 No, non-oral hydrocodone, dihydrocodeine, hydrocodone Yes narcotic analgesics 0.5 500 10 40 100 4 Yes hydromorphone, norhydrocodone No, short hydromorphone hydromorphone Yes narcotic analgesics 2 500 10 30 100 2.4 half-life meperidine meperidine No narcotic analgesics NA NA 100 800 1000 4.5 Yes methadone methadone No narcotic analgesics NA NA 400 600 600 36 Yes morphine, No, short morphine Yes narcotic analgesics 2 500 10 100 100 2.5 hydromorphone half-life oxycodone, oxycodone noroxycodone, Yes narcotic analgesics 2 500 5 100 200 3.5 Yes oxymorphone oxymorphone oxymorphone Yes narcotic analgesics 2 500 NA NA NA 8 Yes No, often diclofenac diclofenac Yes NSAIDs 20 5000 500 3000 50000 1.5 non-oral etodolac etodolac No NSAIDs NA NA 10000 20000 40000 7 Yes No, short fenoprofen fenoprofen No NSAIDs NA NA 30000 60000 1.2E5 2.5 half-life 20000 No, short ibuprofen ibuprofen No NSAIDs NA NA 15000 30000 2 0 half-life indomethacin indomethacin No NSAIDs NA NA 300 1000 4000 7 Yes No, short ketoprofen ketoprofen No NSAIDs NA NA 1000 6000 12000 1.5 half-life No, often ketorolac ketorolac No NSAIDs NA NA 500 3000 5000 7 non-oral No, short meclofenamate meclofenamate No NSAIDs NA NA NA NA NA 1.3 half-life meloxicam meloxicam Yes NSAIDs 5 2000 400 2000 4000 19.5 Yes

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert 6-methoxy-2- nabumetone naphthylacetic No NSAIDs NA NA 8100 21000 NA 23 Yes acid naproxen naproxen No NSAIDs NA NA 20000 50000 2E5 15 Yes oxaprozin oxaprozin No NSAIDs NA NA 97000 2E5 NA 47 Yes piroxicam piroxicam Yes NSAIDs 80 8000 2000 6000 14000 50 Yes sulindac sulindac Yes NSAIDs 40 10000 1000 5000 10000 7 Yes 16000 No, short tolmetin tolmetin No NSAIDs NA NA 10000 80000 3 0 half-life felbamate felbamate Yes anticonvulsants 100 100000 30000 60000 1E5 19 Yes topiramate topiramate Yes anticonvulsants 100 20000 2000 8000 16000 21 Yes zonisamide zonisamide No anticonvulsants NA NA 10000 40000 40000 60 Yes carbamazepine carbamazepine Yes anticonvulsants 40 4000 4000 12000 20000 15 Yes No, short oxcarbazepine licarbazepine No anticonvulsants NA NA NA NA NA 3 half-life eslicarbazepine licarbazepine No anticonvulsants NA NA NA NA NA NA NPD acetate divalproex valproic acid No anticonvulsants NA NA 29000 60000 NA 12.5 Yes valproic acid valproic acid No anticonvulsants NA NA 50000 1E5 1.2E5 18 Yes gabapentin gabapentin Yes anticonvulsants 100 20000 2000 20000 25000 6 Yes pregabalin pregabalin Yes anticonvulsants 40 4000 2000 5000 10000 6 Yes levetiracetam levetiracetam Yes anticonvulsants 0.05 40000 10000 40000 1E5 7 Yes lamotrigine lamotrigine Yes anticonvulsants 80 8000 3000 14000 30000 15 Yes diphen- diphenhydramine No other CNS agents NA NA 50 100 1000 7 Yes hydramine meclizine meclizine Yes other CNS agents 0.4 100 1 45 NA 5.5 Yes domperidone domperidone Yes other CNS agents 0.5 500 10 100 200 14 Yes meto- metoclopramide Yes other CNS agents 0.2 50 9.7 19 NA 5.5 Yes clopramide

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert prochlor- prochlorperazine Yes other CNS agents 2 500 10 50 200 8 Yes perazine promethazine promethazine No other CNS agents NA NA 50 200 1000 11.5 Yes pramipexole pramipexole Yes other CNS agents 0.2 50 0.39 7.17 15 10 Yes ropinirole ropinirole Yes other CNS agents 0.2 50 0.4 6 12 6.5 Yes non-benzodiazepine butabarbital butabarbital Yes 20 20000 1000 15000 NA 100 Yes anxiolytics non-benzodiazepine pentobarbital pentobarbital No NA NA 1000 5000 10000 30 Yes anxiolytics non-benzodiazepine phenobarbital phenobarbital Yes 200 50000 10000 40000 50000 100 Yes anxiolytics primidone, non-benzodiazepine primidone Yes 80 20000 5000 10000 25000 14.5 Yes phenobarbital anxiolytics non-benzodiazepine secobarbital secobarbital No NA NA 1500 5000 7000 22.5 Yes anxiolytics alprazolam alprazolam Yes benzodiazepines 2 500 5 50 100 13.5 Yes chlordiazepoxide, chlordiaz- oxazepam, Yes benzodiazepines 20 5000 400 3000 3500 17.5 Yes epoxide temazepam clonazepam, 7- clonazepam aminoclonazepa Yes benzodiazepines 2 500 4 80 100 40 Yes m diazepam, nordiazepam, diazepam Yes benzodiazepines 5 5000 200 2500 3000 36 Yes oxazepam, temazepam lorazepam lorazepam Yes benzodiazepines 0.4 100 10 15 30 14 Yes oxazepam oxazepam Yes benzodiazepines 8 2000 200 1500 2000 9.5 Yes temazepam, temazepam Yes benzodiazepines 4 400 20 900 1000 9 Yes oxazepam buspirone, 6- non-benzodiazepine No, short buspirone hydroxy Yes 0.2 50 1 4 8 2.5 anxiolytics half-life buspirone

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert non-benzodiazepine eszopiclone eszopiclone Yes 2 500 10 50 150 5 Yes anxiolytics hydroxyzine, non-benzodiazepine hydroxyzine Yes 0.5 500 50 100 100 13.5 Yes cetirizine anxiolytics non-benzodiazepine meprobamate meprobamate Yes 80 20000 5000 10000 15000 11.5 Yes anxiolytics non-benzodiazepine No, short zaleplon zaleplon Yes 2 500 1 100 200 1 anxiolytics half-life non-benzodiazepine zolpidem zolpidem Yes 2 500 80 150 300 2.5 Yes anxiolytics donepezil donepezil Yes other CNS agents 5 100 30 75 75 75 Yes rivastigmine rivastigmine No other CNS agents NA NA 8 20 40 1.5 No, non-oral armodafinil modafinil No other CNS agents NA NA 1 10 NA 15 Yes No, short atomoxetine atomoxetine No other CNS agents NA NA 200 1000 2000 4 half-life dex- No, short methylphenidate No other CNS agents NA NA 13 23 44 2 methylphenidate half-life methylphenidate, No, short methylphenidate Yes other CNS agents 0.5 500 13 22 44 2 ritalinic acid half-life modafinil modafinil No other CNS agents NA NA 1000 1700 3400 11 Yes baclofen baclofen No other CNS agents NA NA 80 400 1100 7 Yes carisoprodol, carisoprodol Yes other CNS agents 40 40000 10000 30000 40000 8 Yes meprobamate cyclobenzaprine cyclobenzaprine Yes other CNS agents 2 500 3 40 400 18 Yes metaxalone metaxalone Yes other CNS agents 8 2000 600 1020 NA 8.5 Yes No, short methocarbamol methocarbamol Yes other CNS agents 160 40000 25000 40000 2.5E5 1.5 half-life No, short tizanidine tizanidine No other CNS agents NA NA 5 45 90 2.5 half-life warfarin warfarin Yes anticoagulants 50 5000 1000 3000 12000 43.5 Yes apixaban apixaban Yes anticoagulants 4 400 40 320 NA 9.4 Yes rivaroxaban rivaroxaban Yes anticoagulants 2 500 NA NA NA 7 Yes

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert dabigatran dabigatran No anticoagulants NA NA 0.5 1.5 NA 14.5 Yes No, short clopidogrel clopidogrel Yes antiplatelet agents 0.05 50 1 6 NA 2.5 half-life dipyridamole, dipyridamole dipyridamole No antiplatelet agents NA NA 100 1500 4000 12 Yes mono-O-beta- glucuronide No, short pentoxifylline pentoxifylline No antiplatelet agents NA NA 500 2000 4000 1.5 half-life ticagrelor ticagrelor Yes antiplatelet agents 40 1000 NA NA NA 7 Yes ticlopidine ticlopidine No antiplatelet agents NA NA NA NA NA 108 Yes hyoscyamine hyoscyamine Yes antiplatelet agents 0.2 50 0.4 6 NA 7.5 Yes No, short cimetidine cimetidine No gastrointestinal agents NA NA 250 3000 30000 3 half-life No, short famotidine famotidine Yes gastrointestinal agents 2 500 20 200 420 3.5 half-life No, short ranitidine ranitidine No gastrointestinal agents NA NA 50 1000 3000 3 half-life No, short esomeprazole omeprazole No gastrointestinal agents NA NA NA NA NA 1.5 half-life No, short lansoprazole lansoprazole No gastrointestinal agents NA NA 60 410 NA 1.5 half-life omeprazole, 5- hydroxy No, short omeprazole No gastrointestinal agents NA NA 50 4000 8000 1 omeprazole, half-life omeprazole acid No, short pantoprazole pantoprazole No gastrointestinal agents NA NA 1533 13800 27600 1.5 half-life No, short rabeprazole rabeprazole No gastrointestinal agents NA NA 200 1800 3600 1.5 half-life No, short dexlansoprazole lansoprazole No gastrointestinal agents NA NA NA NA NA NA half-life

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert sildenafil, N- genitourinary tract No, short sildenafil desmethyl Yes 4 400 50 500 1000 4 agents half-life sildenafil genitourinary tract tadalafil tadalafil Yes 4 1000 90 480 960 17.5 Yes agents genitourinary tract vardenafil vardenafil Yes 0.2 50 2 4 NA 4.5 Yes agents genitourinary tract mirabegron mirabegron Yes 0.4 100 5.25 31.88 NA 50 Yes agents genitourinary tract darifenacin darifenacin Yes 0.4 100 1.5 20 NA 16 Yes agents genitourinary tract oxybutynin oxybutynin Yes 0.2 50 2 4 NA 12.5 Yes agents genitourinary tract solifenacin solifenacin Yes 4 100 NA NA NA 57 Yes agents genitourinary tract No, short tolterodine tolterodine No NA NA 0.78 1.55 NA 2.8 agents half-life hormones/hormone dutasteride dutasteride No NA NA 25 55 NA 840 Yes modifiers hormones/hormone finasteride finasteride Yes 0.2 50 8 10 20 6 Yes modifiers hormones/hormone No, often budesonide budesonide Yes 2 500 8.61 43.05 NA 2.8 modifiers non-oral hormones/hormone No, often dexamethasone dexamethasone No NA NA 50 265 795 6 modifiers non-oral hormones/hormone No, often prednisolone prednisolone No NA NA 500 1000 2000 4 modifiers non-oral hormones/hormone No, short prednisone prednisolone No NA NA NA NA NA 3.5 modifiers half-life metformin metformin No antidiabetic agents NA NA 100 1000 5000 3 Yes alogliptin alogliptin Yes antidiabetic agents 8 2000 61 870 NA 21 NPD linagliptin linagliptin Yes antidiabetic agents 2 500 2.28 4.07 NA 193 Yes No, short saxagliptin saxagliptin Yes antidiabetic agents 0.4 100 7.91 19.75 NA 2.5 half-life

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert sitagliptin sitagliptin Yes antidiabetic agents 4 1000 50 380 720 11 Yes No, short nateglinide nateglinide Yes antidiabetic agents 8 2000 87 1195 NA 2 half-life No, short repaglinide repaglinide Yes antidiabetic agents 0.4 100 4 55 NA 1 half-life canagliflozin canagliflozin Yes antidiabetic agents 8 2000 170 1300 NA 11.9 Yes dapagliflozin dapagliflozin No antidiabetic agents NA NA 6 285 NA 12.9 Yes empagliflozin empagliflozin No antidiabetic agents NA NA 33.81 360.7 NA 9.73 Yes 15000 20000 chlorpropamide chlorpropamide No antidiabetic agents NA NA 30000 37.5 Yes 0 0 glimepiride glimepiride Yes antidiabetic agents 1 1000 90 500 1000 9.5 Yes glipizide glipizide Yes antidiabetic agents 8 2000 100 1000 2000 5 Yes glyburide glyburide Yes antidiabetic agents 4 1000 50 200 600 10 Yes tolbutamide tolbutamide No antidiabetic agents NA NA 45000 1E5 4E5 8 Yes pioglitazone pioglitazone Yes antidiabetic agents 5 2000 388 766 NA 9.5 Yes No, short rosiglitazone rosiglitazone Yes antidiabetic agents 4 1000 100 300 600 4 half-life colchicine colchicine Yes antigout agents 0.2 50 0.3 2.5 5 21.5 Yes febuxostat febuxostat Yes antigout agents 8 2000 35 1450 NA 6.5 Yes 10000 20000 40000 probenecid probenecid No antigout agents NA NA 10 Yes 0 0 0 antihyperlipidemic ezetimibe ezetimibe Yes 0.4 100 5 45 90 30 Yes agents fenofibrate, antihyperlipidemic fenofibrate Yes 20 5000 5000 30000 60000 21 Yes fenofibric acid agents antihyperlipidemic fenofibric acid fenofibric acid Yes 20 5000 5000 11000 NA 20 Yes agents antihyperlipidemic No, short gemfibrozil gemfibrozil No NA NA NA 25 NA 1.1 agents half-life atorvastatin, antihyperlipidemic atorvastatin atorvastatin Yes 0.4 100 1 9 19 19.5 Yes agents lactone

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert antihyperlipidemic No, short pravastatin pravastatin Yes 0.4 100 2.5 6.3 NA 2.9 agents half-life rosuvastatin, antihyperlipidemic rosuvastatin rosuvastatin Yes 0.4 100 5.9 12.4 NA 19 Yes agents lactone simvastatin, antihyperlipidemic No, short simvastatin Yes 0.4 100 2.7 5.6 11.2 2.5 simvastatin acid agents half-life apremilast apremilast Yes miscellaneous agents 20 5000 NA NA NA NA NPD leflunomide leflunomide No miscellaneous agents NA NA NA NA NA 384 Yes No, dosed methotrexate methotrexate Yes miscellaneous agents 2 500 13.3 60 120 7 infrequently dalfampridine dalfampridine No miscellaneous agents NA NA 15 55 NA 5.8 Yes hydroxy- bupropion No miscellaneous agents NA NA 225 1500 2000 11 Yes bupropion varenicline varenicline No miscellaneous agents NA NA 4 5 10 24 Yes vilazodone vilazodone Yes antidepressants 2 500 55 109 NA 25 Yes 1-(3- nefazodone chlorophenyl) No antidepressants NA NA NA NA NA NA NPD piperazine trazodone, 1-(3- trazodone chlorophenyl) Yes antidepressants 10 2000 700 1000 1200 7.5 Yes piperazine duloxetine duloxetine Yes antidepressants 2 500 30 120 240 14 Yes levomilnacipran milnacipran Yes antidepressants 5 500 140 290 NA 12 Yes milnacipran milnacipran Yes antidepressants 5 500 50 110 220 6.5 Yes desvenlafaxine desvenlafaxine Yes antidepressants 4 1000 NA NA NA 11 Yes venlafaxine, venlafaxine Yes antidepressants 4 1000 100 400 1000 5 Yes desvenlafaxine vortioxetine vortioxetine Yes antidepressants 0.4 100 6 27 NA 65.8 Yes citalopram citalopram Yes antidepressants 0.5 500 50 110 220 33 Yes escitalopram citalopram Yes antidepressants 0.5 500 NA NA NA 32 Yes

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert fluoxetine, fluoxetine No antidepressants NA NA 120 500 1000 120 Yes norfluoxetine fluvoxamine fluvoxamine No antidepressants NA NA 60 230 500 20 Yes paroxetine paroxetine No antidepressants NA NA 30 120 240 28 Yes sertraline sertraline Yes antidepressants 0.5 500 10 150 300 23 Yes mirtazapine mirtazapine Yes antidepressants 4 1000 30 80 1000 30 Yes amitriptyline, amitriptyline Yes antidepressants 3 500 80 200 400 19 Yes nortriptyline amoxapine amoxapine Yes antidepressants 5 500 180 600 3000 8 Yes clomipramine, N- clomipramine desmethyl Yes antidepressants 4 1000 90 250 400 23 Yes clomipramine desimipramine desimipramine No antidepressants NA NA NA NA NA 16.5 Yes doxepin doxepin No antidepressants NA NA 10 200 500 16.5 Yes imipramine, imipramine Yes antidepressants 2 500 175 300 300 18 Yes desimipramine nortriptyline nortriptyline No antidepressants NA NA 70 170 300 30 Yes trimipramine trimipramine No antidepressants NA NA 150 300 600 23 Yes paliperidone paliperidone Yes antipsychotics 0.2 50 NA NA NA 24 Yes aripiprazole, aripiprazole dehydro Yes antipsychotics 1 1000 150 500 1000 70 Yes aripiprazole clozapine, N- clozapine desmethyl- Yes antipsychotics 1 400 350 600 1000 14 Yes clozapine iloperidone iloperidone Yes antipsychotics 1 50 5 10 20 25.5 Yes lurasidone lurasidone Yes antipsychotics 0.4 100 22 42 NA 18 Yes olanzapine, olanzapine desmethyl- Yes antipsychotics 2 500 20 80 150 45 Yes olanzapine

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Limit of detection Reference rangeb Quant T1/2 Use for Drug Analytes Medication class (ng/mL) (ng/mL) a c (h) adherenced Low High Low High Alert quetiapine, quetiapine Yes antipsychotics 8 2000 100 500 1000 7 Yes norquetiapine risperidone, No, short risperidone Yes antipsychotics 0.4 100 20 60 120 3 paliperidone half-life ziprasidone ziprasidone Yes antipsychotics 2 500 50 200 400 6 Yes haloperidol, haloperidol haloperidol Yes antipsychotics 0.2 50 1 10 15 24 Yes metab fluphenazine fluphenazine Yes antipsychotics 0.2 50 1 10 15 16 Yes perphenazine perphenazine Yes antipsychotics 0.2 50 0.6 2.4 5 10 Yes thioridazine thioridazine Yes antipsychotics 2 500 100 200 400 30 Yes cetirizine cetirizine No antihistamines NA NA 20 300 2000 8 Yes chlor- chlorpheniramine No antihistamines NA NA NA NA NA 24 Yes pheniramine desloratadine desloratadine Yes antihistamines 0.2 50 2 6 12 22 Yes doxylamine doxylamine No antihistamines NA NA NA NA NA 9 Yes fexofenadine fexofenadine Yes antihistamines 8 2000 100 900 2700 16 Yes levocetirizine cetirizine No antihistamines NA NA NA NA NA NA Yes loratadine, loratadine Yes antihistamines 0.2 50 1 20 40 11 Yes desloratadine dextro- dextro- No, short No other respiratory agents NA NA 10 40 100 3 methorphan methorphan half-life pseudoephedrin pseudoephedrine No other respiratory agents NA NA 500 800 1600 12.5 Yes e montelukast montelukast No leukotriene modifiers NA NA 50 300 600 4.5 Yes roflumilast roflumilast Yes other respiratory agents 0.2 50 1.25 2.4 NA 17 Yes a analytes that are measured quantitatively are reported in ng/mL and shown as “Yes”; analytes that are measured qualitatively are reported as “detected” or “not detected” and shown as “No”; b literature-reported reference ranges from the therapeutic drug monitoring literature compiled from numerous sources; c literature-reported biological half-life of drugs following oral ingestion reported from numerous sources; d whether the drug was included in the 189 medication subset used for assessing adherence; values of NPD denote “not prescribed or detected”, indicating that while they were included in the test panel, they were not prescribed or detected in any of the cohorts.

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eTable 3. Proportion of Samples With Detected Medication, by Medication Category

Proportion Drug class adherenta (N)b Adherence to most prescribed drugs in classc anticoagulants 87% (83) warfarin (91%, 67) alprazolam (71%, 38), clonazepam (86%, 37), lorazepam benzodiazepines 84% (128) (93%, 28) beta-adrenergic metoprolol (89%, 197), carvedilol (76%, 68), atenolol blocking agents 83% (349) (88%, 51) antiarrhythmic agents 82% (55) diltiazem (100%, 34), amiodarone (38%, 13) gabapentin (78%, 114), pregabalin (80%, 30), topiramate anticonvulsants 80% (213) (90%, 20) metformin (84%, 147), sitagliptin (75%, 40), glimepiride antidiabetic agents 80% (263) (80%, 25) antihyperlipidemic atorvastatin (74%, 174), rosuvastatin (77%, 53), ezetimibe agents 78% (280) (93%, 28) citalopram (87%, 95), trazodone (77%, 53), sertraline antidepressants 75% (390) (67%, 52) angiotensin converting enzyme inhibitors 74% (257) lisinopril (73%, 237), benazepril (73%, 11) angiotensin II losartan (75%, 102), valsartan (69%, 32), olmesartan inhibitors 73% (163) (86%, 14) antiadrenergic agents, peripherally acting 73% (63) tamsulosin (73%, 45), doxazosin (50%, 10) hctz (71%, 233), triamterene (79%, 33), torsemide (92%, diuretics 73% (296) 13) non-benzodiazepine anxiolytics 73% (66) zolpidem (71%, 41), hydroxyzine (71%, 14) anti-infectives 71% (34) hydroxychloroquine (76%, 17) narcotic analgesics 70% (123) hydrocodone (70%, 76), oxycodone (71%, 45) antipsychotics 67% (49) quetiapine (64%, 22), aripiprazole (58%, 12) calcium channel blocking agents 66% (217) amlodipine (66%, 169), nifedipine (76%, 41) miscellaneous agents 64% (56) bupropion (69%, 49) acetaminophen (68%, 171), meloxicam (58%, 38), NSAIDs 62% (282) naproxen (54%, 35) cetirizine (59%, 56), loratadine (63%, 43), fexofenadine antihistamines 61% (135) (66%, 32) genitourinary tract oxybutynin (67%, 15), tadalafil (50%, 14), solifenacin agents 60% (43) (80%, 10) cyclobenzaprine (59%, 34), promethazine (11%, 18), other CNS agents 53% (146) diphenhydramine (31%, 16) leukotriene modifiers 50% (50) montelukast (50%, 50) a percent of patient-drug prescriptions in the class that are detected; non-detected prescriptions with prn status are excluded, since failure to detect does not constitute non-adherence; b number of patient-drug prescriptions considered in a; c the most commonly prescribed medications that are members of the class, showing percent adherence and total prescription count across the 3 cohorts; only the top 3 medications by prescription count are shown, provided there were at least 10 prescriptions

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eTable 4. Proportion of Medication Detections Without Evidence of Prescription, by Medication Category

Proportion not in Drug class EHRa (N)b Highest DNP % drugs (20+ detections) c naproxen (84%; 116), ibuprofen (82%; 74), acetaminophen NSAIDs 63% (533) (58%; 279) cetirizine (49%; 65), loratadine (43%; 47), fexofenadine antihistamines 51% (167) (34%; 32) diphenhydramine (83%; 29), meclizine (65%; 34), other CNS agents 50% (170) cyclobenzaprine (33%; 30) morphine (74%; 35), oxycodone (47%; 60), hydrocodone narcotic analgesics 49% (198) (37%; 84) antiplatelet agents 47% (62) clopidogrel (42%; 50) antipsychotics 44% (72) quetiapine (30%; 20) antiarrhythmic agents 42% (101) diltiazem (31%; 49) diazepam (61%; 44), lorazepam (43%; 46), alprazolam benzodiazepines 42% (183) (39%; 44) leukotriene modifiers 40% (42) montelukast (40%; 42) non-benzodiazepine anxiolytics 38% (90) zolpidem (29%; 41) genitourinary tract agents 38% (50) oxybutynin (58%; 24) miscellaneous agents 32% (56) bupropion (26%; 46) anticoagulants 31% (105) warfarin (27%; 83) gabapentin (29%; 125), pregabalin (20%; 30), topiramate anticonvulsants 30% (251) (18%; 22) antihyperlipidemic simvastatin (42%; 128), atorvastatin (26%; 175), pravastatin agents 30% (462) (26%; 43) anti-infectives 27% (37) no single drug with 20 or more detections venlafaxine (32%; 31), trazodone (29%; 58), fluoxetine (29%; antidepressants 27% (401) 31) angiotensin II inhibitors 26% (161) valsartan (29%; 31), losartan (23%; 99) famotidine (45%; 42), pantoprazole (30%; 43), omeprazole gastrointestinal agents 25% (350) (20%; 228) furosemide (30%; 76), hctz (17%; 198), triamterene (13%; diuretics 23% (357) 30) beta-adrenergic metoprolol (22%; 227), atenolol (22%; 58), carvedilol (20%; blocking agents 22% (281) 65) hormones/hormone modifiers 22% (64) finasteride (33%; 21), prednisone (21%; 33) glipizide (36%; 25), glimepiride (33%; 30), metformin (18%; antidiabetic agents 21% (271) 151) antiadrenergic agents, peripherally acting 20% (59) tamsulosin (25%; 44) calcium channel blocking agents 17% (172) amlodipine (18%; 136), nifedipine (11%; 35) angiotensin converting enzyme inhibitors 14% (244) ramipril (30%; 20), lisinopril (12%; 196) a the percentage of all detected drugs that are detected not prescribed (DNP), i.e. not included in patient EHR medication list, across the 3 cohorts; b the total number of drug detections across the 3 cohorts; c medications within the class having the highest rate of detected medications not in the EHR, among those with 20 or more detections across the 3 cohorts; values in red highlight prescription-only drugs with a DNP rate greater than 50%. The notation shows the percent of DNP detections, followed by the total number of detections.

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A acetaminophen hydrocodone metoprolol omeprazole lisinopril clopidogrel

morphine nifedipine Primary indication 10 hydrochlorothiazide coagulation modifiers

colchicine anti-infectives naproxen prednisolone antineoplastics meperidine pramipexole cardiovascular agents oseltamivir central nervous system agents nitrofurantoin ibuprofen gastrointestinal agents hydromorphone 1 pravastatin lamivudine hormones/hormone modifiers prednisone metabolic agents chlorothiazide

sitagliptin miscellaneous agents

olmesartan psychotherapeutic agents levetiracetam respiratory agents Percent detected, ED 0.1 genitourinary tract agents

rivaroxaban

montelukast 0.01 0.01 0.1 1 10 Percent detected, residuals B narcotic analgesics 5.1 angiotensin converting enzyme inhibitors 3.3 calcium channel blocking agents 2.8 beta adrenergic blocking agents 2.7 anticoagulants 2.5 antiarrhythmic agents 2.4 other CNS agents 2.4 anticonvulsants 2.2 benzodiazepines 1.9 overall 1.8 antidiabetic agents 1.5 non-benzodiazepine anxiolytics 1.5 diuretics 1.5 antidepressants 1.4 antihistamines 1.4 NSAIDs 1.4 angiotensin II inhibitors 1.3 antiadrenergic agents, peripherally acting 1.3 antihyperlipidemic agents 1.2 antipsychotics 1.1

0 1 2 3 4 5 Percent detected ED / Percent detected residuals eFigure 1. Medication Detection Rate in Two Cohorts. A) 245 individual medications detected in 1 or more subjects in the emergency department (ED) and/or residuals cohorts, expressed as a percentage of subjects and shown on a log scale. The ED and residuals cohorts comprised 296 and 1000 subjects, respectively. Medications detected in only one cohort are shown at 0.01 on the opposite axis, an arbitrary value to avoid taking log of zero. Because detection counts are discrete, percentage values cluster along the axes for low detection count drugs and points are jittered to show multiple drugs at the same position (e.g. 12 medications detected in 1/296 subjects in ED vs. 0/1000 subjects in residuals cohorts are shown at x = 0.01 and y = 0.34 %). In total, 73 drugs (boxed in blue) were detected exclusively in one of the two cohorts, and a further 28 drugs (boxed in red) were detected once in one or both cohorts. The dashed line denotes the overall increased detection rate of 1.8x in the ED vs. residuals cohorts, and selected drugs deviating from the trend are labelled by name. B) Analysis of relative detection rates in ED vs. residuals cohorts when aggregating medication detections by drug class; only classes represented by 10 or more detections in both cohorts are shown.

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5 R 2 = 0.78

angiotensin converting enzyme inhibitors anticoagulants

narcotic analgesics antiadrenergic agents, peripherally acting

calcium channel blocking agents antipsychotics antiarrhythmic agents beta-adrenergic blocking agents 3 antihyperlipidemic agents

diuretics CNS agents, others

NSAIDs anticonvulsants overall ED vs residuals prescription rate

2 non-benzodiazepine anxiolytics, sedatives, and hypnotics

benzodiazepines antidiabetic agents

antidepressants

angiotensin II inhibitors 1 antihistamines

1 2 3 4 5 ED vs residuals detection rate

eFigure 2. Comparison of Differential Prescription and Detection Rates in ED vs Residuals Cohorts. For each drug class, the total number of prescriptions or detections was obtained and expressed as a percentage (e.g. 10 detections in 1000 residuals subjects = 1% detection rate). The ratio of ED vs residuals prescription rates (ordinate) is compared to the ratio for detection rates (abscissa); the linear regression fit used all classes except for the outlier of narcotic analgesics, for which the ratio of ED vs residuals detection rate is notably higher than the ratio of prescription rates.

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p = 0.13 A p = 7e-10 p = 2e-12

100 80 60

40 20 Percent adherence 0 Residuals Gastro. Care ED care Count 351 46 246

Avg 73 91 70

B Residuals Gastroenterology Care ED care 100 80 60 40

20 p = 0.43 p = 0.67 p = 0.13 Percent adherence 0 Gender F M F M F M Count 239 112 28 18 132 114 Avg 72 75 90 92 67 72

C Residuals Gastroenterology Care ED care 100 80 60 40 20 Percent adherence 0 Age <40 40s 50s 60s 70s ≥80 <40 40s 50s 60s 70s >80 <40 40s 50s 60s 70s ≥80 Count 30 36 68 110 63 44 1 8 24 11 2 11 31 84 79 31 10 Avg 67 62 71 72 80 84 67 93 90 92 89 51 63 71 73 69 70

D Residuals Gastroenterology Care ED care 100 80 60 40 20 Percent adherence 0 Prescribed drugs 3 4 5 6 7 8-10 11+ 3 4 5 6 7 8-10 11+ 3 4 5 6 7 8-10 11+ Count 108 84 56 39 35 25 4 6 12 7 6 7 7 1 46 37 51 39 27 35 11 Avg 69 73 76 73 79 76 75 94 92 97 86 92 85 64 72 68 69 72 69 66 76

eFigure 3. Adherence to Prescription Drugs (legend on next page)

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The percentage of prescribed drugs from the 189 drug subset (methods) that were detected in each subject was calculated. Only subjects prescribed 3 or more drugs from the subset were included. Percent adherence for subjects analyzed by A) cohort, B) gender, C) age, and D) number of prescribed drugs. For panels A and B, p-values were obtained from Welch two sample t-tests. For C, adherence increased modestly with age in the residuals (R2 = 0.03, F(1,346) = 11.5, p-value = 0.0007) and ED cohorts (R2 = 0.02, F(1,244) = 5.6, p-value = 0.02), but not the GE care cohort (R2 = 0.00, F(1,44) = 0.04, p-value = 0.84). For D, adherence increased with number of prescribed drugs in the GE care cohort (R2 = 0.10, F(1,44) = 5.1, p-value = 0.03) but not the residuals (R2 = 0.00, F(1,349) = 2.31, p-value = 0.13) or ED cohorts (R2 = 0.00, F(1,244) = 0.001, p-value = 0.97).

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90 r2=0.904rr2=0.904²=0.90

beta-adrenergic blocking agents

benzodiazepines

anticonvulsants antiarrhythmic agents

antihyperlipidemic agents 80 anticoagulants antidiabetic agents antiadrenergic agents, peripherally acting antidepressants diuretics anti-infectives angiotensin II inhibitors

angiotensin converting enzyme inhibitors 70 non-benzodiazepine anxiolytics

genitourinary tract agents narcotic analgesics antipsychotics calcium channel blocking agents Percent adherence (naive)

antihistamines NSAIDs

60 miscellaneous agents

other CNS agents leukotriene modifiers 50

-1.5 -1 -0.5 0 0.5 Logistic regression model coefficient

eFigure 4. Comparison of Naïve Estimates of Adherence by Medication Class vs. Coefficients From Logistic Regression Modelling. The logistic regression model fit from 3255 patient- prescribed medication pairs (from the 189 drug adherence subset) had the form: detected (yes/no) ~ cohort + age + adherence to other meds + drug class; cohort was coded as a 3-level categorical variable, and drug class as a 23-level categorical variable. Adherence to other medications ranged from 0 to 100% and excluded the medication represented in a given patient-medication pair. By definition, the first category for cohort (ED) and drug class (anti-infectives) have coefficient = 0 and p-value = 1. The coefficients and p-values for inclusion of covariates in the model were as follows: cohort=primary care (0.79, 3e-04), cohort=residuals (0.16, 0.07), age (0.008, 0.03), adherence to other meds (0.025, <2e-16). All coefficients were positive, indicating increased probability of adherence for the named cohorts relative to ED patients, and increasing probability of adherence with age / adherence to other meds. The coefficients shed light on the effect size of a given increase in the variable: a 1 year increase in age increases the adherence log odds ratio by 0.008, therefore a 10 year increase in age translates to an odds ratio of 1.08, or a ~2% increase in probability of adherence. Likewise, a 10% increase in adherence to other meds translates to an odds ratio of 1.3 or a ~6% increase in probability of adherence to a given drug.

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antihistamines (106, 44) r2=0.599rr2=0.599²=0.60 60

50 narcotic analgesics (64, 126) NSAIDs (377, 128)

other CNS agents (98, 66) antiarrhythmic agents (55, 41)

40 antiplatelet agents (22, 40)

antipsychotics (46, 23)

benzodiazepines (115, 64)

30 non-benzodiazepine anxiolytics (57, 25)

antidepressants (264, 113) antihyperlipidemic agents (279, 128) Percent DNP, ED Percent DNP, antidiabetic agents (164, 75)

20 anticonvulsants (147, 94)

angiotensin II inhibitors (107, 42)

gastrointestinal agents (205, 117) diuretics (213, 116) anticoagulants (57, 43) 10 beta-adrenergic blocking agents (203, 158)

calcium channel blocking agents (86, 71)

angiotensin converting enzyme inhibitors (115, 105)

30 40 50 60 70 Percent DNP, residuals

eFigure 5. Comparison of Detection Rates for Medications not Listed in Subjects’ Health Record in Two Cohorts. For each drug class, the percent of medications that were detected but not prescribed (DNP; i.e. detected medications not listed in the EHR) was compared between the residuals and ED cohorts. The percentage was calculated as (number of DNP drugs) / (number of detected drugs) x 100. Only drug classes with 20 or more detections in each cohort were included. Labels shown the number of detections in the residuals and ED cohorts, respectively.

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