Course Syllabus


Alec Walker                   


FXB Building, Room G11

Mondays and Wednesdays 1:30 – 3:20 pm

Office hours: after class and by appointment


The goal of this course is to introduce students to the most important issues of pharmacoepidemiology.  To this end, we will emphasize the ways in which the observational study of drugs can draw on standard epidemiologic technique, and explore the ways in which drugs present unique research problems and opportunities.


Material will be taught through seminars, case studies, and group projects.  Students will be chosen in class to summarize assigned papers for that class session or to address the questions presented in the syllabus.  In both cases, your response will be the starting point for a discussion in which all your classmates are expected to participate.  Class participation is not part of your grade, but it is the vehicle for everyone’s learning.


There will be short lectures at the beginning of many of the classes.  The material is denoted in the Syllabus by a file name in bold letters. There is a link to corresponding file on the course website.  The first number in the name corresponds to the class number on the Schedule, below.  For example, 01 PE Intro 2016 is the slide deck for the first class.  I will post the lectures to the course website at least a week in advance of the class.


For the class discussions to be lively readings need to be done in advance of the class.  Each reference to a reading in this syllabus and on the course website has an embedded hyperlink that takes you either to the article or to the article’s page in the publishing journal.  The links go through the Countway Library of Medicine. You will need to have Countway Library access to get to the links. If you do not have Countway access, you can still get the citation in your usual way.  References to unpublished readings and to study questions for each reading are indicated in the Syllabus in the same way that lectures are: by a file name in bold letters, and are associated with a link on the course website.  For example: 02 RotaShield Case Study 2016.   

When there are two documents posted for the same class, they will be designated with an “a” and “b” after the class number.


Citations marked in this Syllabus as “References” indicate supplementary material, used in the lectures or exercises.  You are not expected to have read these before class.  These should be considered as optional reading.


There will be three short essays (500-word limit), to be done in teams.  Essays will be assigned at the end of each Section of the class (see below).  Topics will be drawn from current news or medical literature.  Any number of students may work together on an essay, and the names of all students taking ownership for the essay should appear at the beginning of the essay.  Essays are due one week after assignment, and should be submitted as an attachment to an email addressed to 

As the file name for your submission, please use the designation “Epi221”, a hyphen, the assignment number and one author’s family name (written with English letters) and first initial.  For example, if Luis Alberto García Rodríguez’s group submitted a response to the first assignment, they would name the file “Epi221-1GarciaL”.  There is no penalty for getting this wrong, but it makes your instructor’s life much simpler if you follow the rule exactly, as he sorts material on his computer using file names.

The essays are graded on a ten-point scale, corresponding to work that

            10, 9, 8 (A, A, A-)        Would be acceptable from a professional colleague

            7, 6 (B+, B)                  Shows evidence of colleagues-in-training

            5 (C)                            Would be insufficient for ordinary scientific interchange

            Below 5 (Fail) Is unacceptable or incomplete.

The final class grade is a simple average of the three essay grades, rounded to the nearest integer.  In the past, most students have performed at level 7 (B+) or above.


I will update the Syllabus and the corresponding material on the website throughout the course. If you download this document be sure to check periodically on the class web page that you have the latest version.  The date is in the footer.


Many of the examples that we will discuss are ones that I have worked on professionally as a researcher or as a consultant since leaving full-time academic work.  Current or recent past clients that have an interest in the material include Astellas, Daiichi Sankyo, Eisai, GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Purdue, Reagan Udall Foundation for the FDA, Roche, UK Committee on the Safety of Medicines, US Food and Drug Administration, US Department of Justice.







The Problem of Drug Safety

August 31


Research Designs in Pharmacoepidemiology

September  7


Case Study: RotaShield and Intussusception in Infants



Case Reports and Case Series



Formal Designs for Safety Evaluation



Randomized Controlled Trials



First assignment distributed



Cohort Studies for Risk



Cohort Studies for Rates



First assignment due



Case-Control Studies



Second assignment distributed



Case-Only Designs

October 3


Confounding by indication



Propensity scores


Second assignment due



Third assignment distributed



 (No class – Columbus Day holiday)



Instrumental Variables



Third assignment due



Scanning Databases for Safety



Genetic Susceptibility to Drug Adverse Reactions




Class Synopsis

Documents that are available on the course website are listed in bold typeface surrounded by brackets.

Inference from Informal Designs


1 Course Introduction – Research Designs

August 31


We will begin to consider all the issues that the course grapples with.


Read at your leisure:

Jick H, García Rodríguez LA, Pérez-Gutthann S.  Principles of epidemiological research on adverse and beneficial drug effects.  Lancet 1998;352:1767-70


The "Pharmaco" in Pharmacoepidemiology and Research Designs [01 PE Intro 2016]      

References for examples used in the lecture.  None of these are required reading.

Bell C, Charavarty A, Gruber S, Heckbert SR, Levenson M, Martin D, Nelson JC, Sinheiro S, Psaty BM, Reich CG, Schneeweiss S, Shoaibi A, Toh S, Walker AM. Characteristics of study design and elements that may contribute to the success of electronic safety monitoring systems.  Pharmacoepidemiol Drug Saf 2014 Nov;23(11):1223–1225

Lindberg G, Bingefors K, Ranstam J, Råstam L, Melander A. Use of calcium channel blockers and risk of suicide: ecological findings confirmed in population based cohort study. BMJ. 1998 Mar 7;316(7133):741-5

Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995 Aug 23-30;274(8):620-5

Walker AM, Jick H, Porter J. Drug-related superinfection in hospitalized patients. JAMA. 1979 Sep 21;242(12):1273-5

Walker AM. Pattern recognition in health insurance claims databases. Pharmacoepidemiol Drug Saf. 2001 Aug-Sep;10(5):393-7


2 Case Study: RotaShield and Intussusception in Infants

September 7


Events quickly get ahead of the capacity for formal research in drug safety.  We will examine the early months of the problem of intussusception in infants who received the vaccine RotaShield.


02 RotaShield Case Study 2016

Please read this document before class, think about the answers to the questions, and discuss with a colleague.


ACIP. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices ACIP).  MMWR Recommendations and Reports, March 19, 1999 / 48(RR-2);1-23

Alkoshi S, Maimaiti N, Dahlui M. Cost-effectiveness analysis of rotavirus vaccination among Libyan children using a simple economic model. Libyan J Med. 2014 Dec 9;9:26236

Suspension of rotavirus vaccine after reports of intussusception – United States, 1999. Morbidity and Mortality Weekly Report 2004;53:786-9 

Murphy TV, Gargiullo PM, Massoudi MS et al. Intussusception among infants given an oral rotavirus vaccine.  N Engl J Med 2001;344:564-72

Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD; WHO-coordinated Global Rotavirus Surveillance Network. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis. 2012 Feb;12(2):136-41

Zanardi LR, Haber P, Mootrey GT, Niu MT, Wharton M. Intussusception among recipients of rotavirus vaccine: reports to the vaccine adverse event reporting system. Pediatrics. 2001 Jun;107(6):E97


3 Case Reports and Case Series

September 12


Spontaneous reports to regulatory authorities are the backbone of safety surveillance.  We will review informal causality assessment from a case report.  We will also review a population based case series to understand what inferences can be made from groups of cases, and read the US FDA’s guidance on case reports and case series.


Feenstra J, van Drie-Pierik RJHM, Lacié CF, Stricker BHCh.  Acute myocardial infarction associated with sildenafil.  Lancet 1998;352:957-8

Guidance for Industry. Good Pharmacovigilance Practices and Pharmaco-epidemiologic Assessment. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).

Rubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, Wu TT, Murray JA. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012 Aug;87(8):732-8

Study Questions

03 Case Report Case Series Study Questions 2016


Formal Designs for Safety Evaluation

4 Randomized Controlled Trials

September 14


The RCT provides the paradigm of rigorous design, and RCTs are increasingly being used to evaluate primary safety endpoints.  The sacrifices required to get a feasible study accomplished may limit its generalizability.  Accommodating design to the ethical necessities of good patient care may introduce a divergence between the study concept and the reality of what was investigated.  We will examine the trial that began the Vioxx controversy and a large vaccine safety trial.


Core Characteristics of Randomized Controlled Trials 04a RCTs Lecture 2016

Reference for the example used in the lecture

Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS; REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010 Apr 1;362(13):1192-202


Chey WD, Webster L, Sostek M, Lappalalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain.  N Engl J Med 2014; 370:2387-2396

Study Questions

04b RCT Study Questions 2016


5 Cohort Studies for Risk

September 19


Cohort studies provide the fundamental measures of risk and rates.  This class will evaluate the components of ad hoc safety studies of risk, in which the study subjects have a fixed exposure classification at a point in time, and the cumulative occurrence of the event is identified over a short, fixed time horizon.


05a Cohort Risk Lecture 2016

References for the examples used in the lecture

Gray DT, Fyler DC, Walker AM, Weinstein MC, Chalmers TC.  Clinical outcomes and cost of transcatheter vs. surgical closure of patent ductus arteriosus. N Engl J Med. 1993;329:1517-1523

Gao S, Juhaeri J, Dai WS.  The incidence rate of seizures in relation to BMI in UK adults. Obesity. 2008;16:2126-2132

Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettit D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol. 2006;17: 2293–2298

The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333:5-10

Brookhart MA, Walker AM, Lu Y, Polakowski L, Li J, Paeglow C, Puenpatom T, Izurieta H, Daniel GW. Characterizing vaccine-associated risks using cubic smoothing splines.  Am J Epidemiol. 2012 Nov 15;176(10):949-57

Jain A, Marshall J, Buikema A, Bancroft T, Kelly JP, Newschaffer CJ. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA. 2015 Apr 21;313(15):1534-40


Desai RJ, Huybrechts KF, Hernandez-Diaz S, Mogun H, Patorno E, Kaltenbach K, Kerzner LS, Bateman BT. Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study. BMJ. 2015 May 14;350:h2102

Study Questions

05b Cohort Risk Questions 2016


6 Cohort Studies for Rates

September 21

People using medical products typically move through a series of exposure levels.  These may be defined by dose of exposure, alternative therapies, time since first or last exposure.  The usual technique for keeping track of these changes is to calculate dwell-time in a particular, fully classified status, and to add up individual dwell-times to a collective measure called “person-time.”  Counts of vents divided by person-time give rates.


06a Cohort Rate Lecture 2016

References for the examples used in the lecture

Brookhart MA, Walker AM, Lu Y, Polakowski L, Li J, Paeglow C, Puenpatom T, Izurieta H, Daniel GW. Characterizing vaccine-associated risks using cubic smoothing splines.  Am J Epidemiol. 2012 Nov 15;176(10):949-57

Gao S, Juhaeri J, Dai WS.  The incidence rate of seizures in relation to BMI in UK adults. Obesity. 2008;16:2126-2132

Jain A, Marshall J, Buikema A, Bancroft T, Kelly JP, Newschaffer CJ. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA. 2015 Apr 21;313(15):1534-40

The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333:5-10

Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettit D. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol. 2006;17: 2293–2298


Basson M, Mezzarobba M, Weill A, Ricordeau P, Allemand H, Alla F, Carbonnel F. Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. Gut. 2015 Aug 6. pii: gutjnl-2015-309690. doi:10.1136/gutjnl-2015-309690. [Epub ahead of print]

Study Questions

06b Cohort Rate Questions 2016


7 Case-Control Studies

September 26


Case-control studies confront the problem of identifying a complete case series, sampling the source population, and gathering apposite data.


07a Case-Control Studies Lecture 2016

References for examples used in the lecture

Johannes CB, Schneider GA, Dube TJ, Alfredson TD, Davis KJ, Walker AM. The risk of nonvertebral fracture related to inhaled corticosteroid exposure among adults with chronic respiratory disease. Chest. 2005 Jan;127(1):89-97

Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA.  Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study.  Lancet 2005;365:475-81


Paulozzi LJ, Kilbourne EM, Shah NG, Nolte KB, Desai HA, Landen MG, Harvey W, Loring LD. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med. 2012 Jan;13(1):87-95

Study Questions

07b Case-Control Study Questions 2016


8 Case-Only Designs

September 28


Case-crossover studies are a variant of case-control studies in which earlier time in each case’s personal history represents the comparator against which to judge the case’s exposure immediately prior to case onset.   They are the most commonly used variant of a larger class of self-controlled designs.


08a Self-Controlled Studies Lecture 2016


Chang CH, Chen HC, Lin JW, Kuo CW, Shau WY, Lai MS. Risk of hospitalization for upper gastrointestinal adverse events associated with nonsteroidal anti-inflammatory drugs: a nationwide case-crossover study in Taiwan. Pharmacoepidemiol Drug Saf. 2011 Jul;20(7):763-71

Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991 Jan 15;133(2):144-53

Mueller JE. Triggering of cardiac events by sexual activity: findings from a case–crossover analysis Am J Cardiol 2000;86(2, Suppl 1):14F–18F

Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, Zanardi LR, Setia S, Fair E, LeBaron CW, Wharton M, Livingood JR. Rotavirus Intussusception Investigation Team. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344:564-72

Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics: the self-controlled case series method. Statistics in Medicine. 2006; 25(10): 1768-97


Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BE, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, Reynolds RF. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015 Jan;12(1):139-51

Study Questions

08b Self-Controlled Study Questions 2016


9 Confounding by Indication

October 3


An important drawback in observational studies of drug effects is the inevitable association between exposure and the medical indication for the exposure.  We will discuss an example, the association between cimetidine and gastric cancer, which has been the object of a long-standing discussion and has only recently been resolved.  In today’s class, we will introduce propensity scores and in the next class discuss how propensity scores permit for control of unmeasured factors by proxy.


9a Confounding Indication Lecture 2016


Walker AM.  Confounding by indication.  Epidemiology 1996;7:335-336

Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP.  Cimetidine and gastric cancer: preliminary report from post-marketing surveillance study. Brit Med J 1982;285:1311-1313

Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP.  Postmarketing surveillance of the safety of cimetidine: mortality during second, third, and fourth years of follow up. Brit Med J 1985;291:1084-8

Study Questions

9b Confounding Indication Study Questions 2016


10 Propensity Scores

October 5


The rich data in large linked databases make study designs that incorporate these data at an early phase especially attractive.  We will examine propensity scores here.  Propensity scores have use in the control of confounders and of proxies for confounders.


10a Propensity Lecture 2016


Brookhart MA, Stürmer T, Glynn RJ, Rassen J, Schneeweiss S.  Confounding control in healthcare database research: challenges and potential approaches.  Med Care. 2010 Jun;48(6 Suppl):S114-20


Seeger JD, Williams PL, Walker AM.  An application of propensity score matching using claims data.  Pharmacoepidemiol Drug Saf. 2005 Jul;14(7):465-76

Study Questions

10b Propensity Study Questions 2016


October 10

No class.  Columbus Day Holiday.


11 Instrumental Variables


October 12


Economists have faced the problem of unmeasured predictors for years, but their techniques are on recently gaining currency in the biomedical literature.  The core problem is identifying a suitable instrument and in demonstrating that the instrument actually meets requirements for unbiased estimation.


Pratt N, Roughead EE, Ryan P, Salter A. Antipsychotics and the risk of death in the elderly: an instrumental variable analysis using two preference based instruments. Pharmacoepidemiol Drug Saf. 2010 Jul;19(7):699-707


11a Instrumental Variables Lecture 2016


Brookhart MA, Rassen JA, Schneeweiss S. Instrumental variable methods in comparative safety and effectiveness research. Pharmacoepidemiol Drug Saf. 2010 Jun;19(6):537-54

Cole JA, Norman H, Weatherby LB, Walker AM.  Co-pay and adherence in congestive heart failure: Impact on cost and outcomes. Pharmacotherapy. 2006;26(8):1157–1164

Hernán MA, Robins JM. Instruments for causal inference: An epidemiologist’s dream?  Epidemiology. 2006;17: 360 –372

 Study Questions

11b Instrumental Variables Study Questions 2016


12 Scanning Databases for Drug Safety

October 17


The availability of large linked data resources that contain drug utilization and health outcomes over many years raises the possibility of systematic exploration. Conceptually, this is the first step in liberating ourselves from traditional and even new epidemiologic study paradigms that have been driven by limitations in access to data.

We will take this time to review your work on evaluating the Danish data for a particular drug safety question (Assignment 3), and we’ll explore some of the principles that we might use going forward.


Pottegård A, Friis S, Christensen Rd, Habel LA, Gagne JJ, Hallas J. Identification of associations between prescribed medications and cancer: A nationwide screening study. EBioMedicine. 2016 May;7:73-9

Walker AM. Orthogonal predictions; Follow-up questions for suggestive data. Pharmacoepidemiol Drug Saf. 2010 May;19(5):529-32

Walker AM, Wise RP. Precautions for proactive surveillance. Pharmacoepidemiol Drug Saf. 2002;11:17-20

Walker AM. Pattern recognition in health insurance claims databases. Pharmacoepidemiol Drug Saf. 2001;10:393-7



13 Genetic Susceptibility to Drug Adverse Reactions

October 19


Many “idiopathic” drug adverse events may have a genetic origin.  We will investigate the discovery and application of one such pattern.


Find abacavir in the Table of Pharmacogenomic Biomarkers in Drug Labels on, and follow the links to find the Medication Guide and Other Important Information from FDA.  For interest you might also want to scan through "Approval History, Letters, Reviews, and Related Documents" and "Label Information."


13 Genetic Studies Lecture 2016


Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002 Mar 2;359(9308):727-32

Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S.  Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV Cohort Study. Clin Inf Dis 2006;43:99–102

Mallal S, et al for the PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79

Study Questions

This last class is likely to coincide with final or mid-term examinations in other courses.  The study questions have therefore been designed to be entirely self-contained.  Come even if you haven’t been able to do the readings.


Course Summary:

Date Details Due