9/28/15 Study Design Considera1ons in Clinical Pharmacy Ludmila Bakhireva, MD, PhD, MPH Pree Sarangarm, PharmD, BCPS Learning Objec1ves Describe the features, advantages and disadvantages of the observa1onal study designs Explain why the overall study design is important when evalua1ng studies & applying their findings to prac1ce Given a research hypothesis, be able to iden1fy the most appropriate study design to address a clinical research ques1on. 1
9/28/15 Study Design Strategies Study Designs Analy0c Descrip0ve - Correla1onal (ecologic) - Case reports - Case series - Cross- sec1onal surveys Observa0onal: - Case- control - Cohort Interven0on - Clinical trials COHORT STUDY DESIGN 2
Cohort Studies Cohort is a group of persons with similar characteris1cs Cohort study is analysis of a group of persons with similar characteris1cs studied over 1me. Cohort Study Design Target Population Unexposed Exposed Outcome Follow up over time for the development of an outcome Outcome Yes No Yes No Incidence in unexposed: 2/5=0.4 Incidence in exposed: 4/5=0.8 3
Two Major Types of Cohort Studies Prospec0ve Cohort: A cohort is assembled at the present 1me & followed up toward the future Retrospec0ve (historical) Cohort: A cohort is iden1fied and assembled in the past on the basis of exis1ng records and is followed to the present 1me. Two Major Types of Cohort Studies Prospec1ve Cohort Risk + Risk - How many developed the disease? Risk+ Risk - How many developed the disease? Retrospec1ve Cohort Past Today Future 4
Retrospec1ve vs. Prospec1ve Cohort Study Advantages of retrospec1ve study: Can be conducted quickly & cheaply Efficient for diseases with long latency Disadvantages of retrospec1ve study: Informa1on on exposure should be available from pre- exis1ng records Completeness of informa1on? Informa1on on poten1al confounders might not be available in the same records Adapted from Hennekens and Buring. Epidemiology in Medicine. LiYle, Brown, and Company. Boston/Toronto; 1987. General Steps in a Cohort Study Formulate a research hypothesis Define the cohort (study popula1on) Ascertain the exposure Select exposed & unexposed groups Determine the follow- up period Determine the outcome Es1mate a measure of associa1on between exposure and outcome 5
Sources of Exposure Data Records collected independently of the study (e.g., medical records, claims data) Informa1on supplied by the subjects (ques1onnaires, interviews) Medical examina1on Direct measurements Poten1al problem: Incomplete informa1on changes in exposure level over 1me Sources of Outcome Data Data should be complete, comparable, and unbiased Sources: Exis1ng records (medical records, death cer1ficates) Ques1onnaire Direct medical examina1on Poten1al problems: Are the same diagnos1c criteria applied? Are the same diagnos1c procedures applied to both exposed and unexposed groups? 6
Sample Size Considera1ons in Cohort Studies Example: Pre- clinical data for a new NSAID raised concerns about possible hepatotoxicity The company wants to conduct a cohort study to determine the risk of: abnormal liver func0on tests hepa00s cholesta0c jaundice Which outcome will require the largest sample size? Adapted from BL Strom. Pharmacoepidemiology. 2002 by John Wiley & Sons Ltd. 3rd edi1on. Sample Size Considera1ons in Cohort Studies Disease Incidence in unexposed N in exposed group N in unexposed group Abnormal liver function tests 1% 2,319 2,319 Hepatitis 0.1% 23,518 23,518 Cholestatic jaundice 0.01% 235,500 235,500 Rare outcome will require large sample size (N) 7
Major Advantages The temporal rela1onship between the risk factor & disease can be established Can es1mate the incidence of disease and risk! Can study mul1ple effects (outcomes) of a single risk factor Major Disadvantages Can be very expensive & 1me consuming (might need to follow large numbers of subjects for a long 1me) Not good for rare diseases or disease with long latency Lost to follow- up can introduce bias 8
When a Cohort Study Is Warranted? Rare or unusual exposures (risk factors) When mul1ple effects (outcomes) of a single factors need to be evaluated When exposure needs to be carefully quan1fied When RCT is unethical When a Cohort Design is Not Desirable For diseases with long latency period For rare diseases When mul1ple exposures need to be studied 9
9/28/15 CASE- CONTROL STUDIES Case- Control Study A retrospec(ve study where an inves1gator compares propor1on of cases exposed to a risk factor with propor1on of controls exposed to a risk factor. 10
Case- Control Study Design Two groups of people are selected Cases: subjects with the disease Controls: subjects without the disease Inves1gator looks backward in 1me to iden1fy the presence or absence of exposure/risk factors among cases and controls Case- Control Study Design Target Popula1on Controls (Disease/Outcome absent) Cases (Disease/outcome present) Exposure Determine the presence or absence of the exposure(s) in the past Exposure Yes No Yes No Odds of exposure among controls Odds of exposure among cases 11
Case- Control Study Design Exposure Status Outcome + Outcome - Past Today Future Difference between Case- Control & Cohort Studies Prospective Cohort Exposure+ Exposure - How many developed the disease? Exposure+ Exposure - How many developed the disease? Retrospective Cohort Exposure Status Outcome + Outcome - Case-Control Study Past Today Future 12
Advantages of Case- Control Studies Good for disease with long latency Cost- and 1me- efficient Good for rare diseases Allows evalua1on of mul1ple risk factors Disadvantages of Case- Control Studies Selec1on bias (differen1al selec1on of cases & controls) Informa1on bias (differences in collec1on of informa1on in two groups) Recall bias Misclassifica1on of disease and/or exposure status Interviewer bias Do not allow calcula1on of incidence & RR 13
Informa1on Bias is a Par1cular Concern Major Types of Bias Selec0on Bias A distor1on in the measure of associa1on resul1ng from the manner in which subjects are selected into the study popula1on (results differ from what you d have goyen if you had enrolled the en1re target popula1on). Informa0on Bias A flaw in measuring exposure or outcome that results in collec1on of incorrect informa1on from subjects. 14
Confounding: Defini1on Confusion of effects (K. Rothman) A confounding variable, or confounder, is an extraneous factor that wholly or par(ally accounts for the observed effect of the risk factor on disease status (M. Woodward) Distor1on of the associa1on that occurs due to the effect of an extraneous factor (confounder) Consider This Example NSAIDs prescrip0on as analgesics Pa1ents with a history of GI irrita1on or hemorrhage Pa1ents without such a history Prescribed COX- 2- selec1ve NSAIDs Prescribed non- selec1ve NSAIDs Which group will have a higher incidence of GI hemorrhage? 15
Confounding by Indica1on Confounding by the reason of prescrip1on Confounding by underlying disease severity Pa1ents with the worst prognosis are allocated preferen1ally to a par1cular treatment Controlling for Confounding In the Study Design Restric1on Matching Randomiza1on (interven1on studies only) In the Analysis Stra1fica1on Mul1variate analysis 16
9/28/15 CASE DISCUSSION Case 1: Predictors of Hospital Acquired VTE Aner Surgery The goal of this study is to assess the rela1onship between missed pharmacologic VTE prophylaxis doses and development of hospital acquired VTE in surgical pa1ents 17
Case 1: Predictors of Hospital Acquired VTE Aner Surgery What is exposure of interest? What is the outcome? How prevalent is the outcome? How prevalent is exposure? Case 1: Predictors of Hospital VTE Acquired Aner Surgery Can this research ques1ons be answered in a Clinical Trial? What would be the interven1on? Can this ques1on be addressed in a : Cross- sec1onal study? Cohort study? Case- control study? 18
Case 1: Predictors of Hospital VTE Aner Surgery Poten1al informa1on bias? How # of missed doses for VTE prophylaxis can be captured? What other confounders should be considered? Case 2: The effect of Postopera1ve IV Acetaminophen Administra1on on the Reduc1on in Opioid Use Aner the Knee Replacement Surgery. What is the objec1ve of this study? Exposure of interest Main outcome Other important risk/protec1ve factors to consider 19
Case 2: The effect of Postopera1ve IV Acetaminophen Administra1on on the Reduc1on in Opioid Use Aner the Knee Replacement Surgery. Can this ques1on be addressed in a : Cross- sec1onal study? Cohort study? Case- control study? The best study design? 20