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Study Designs - Case control design by Dr Amita Kashyap
- 1. Study Designs in Medical Research Amita kashyap
- 2. Epidemiological Study Designs Descriptive Observational Analytical Population Ecological Individuals Case Reports Case Series Cross Sectional Interventional Experimental Observational Case Control Cohort Prospective & Retrospective Cross Sectional
- 4. II. Experimental studies Controlled trials •Parallel or concurrent controls –Randomized –Not randomized •Sequential controls –Self-controlled –Crossover •External controls (including historical) Studies with no controls
- 5. Hierarchy of Epidemiologic Study Design
- 9. Ecological Fallacy – Not individual Data Correlation btw Dietary Fat Intake & Breast Cancer by Country
- 10. Average Annual Incidence Rate and Relative Risk of Acute Lymphocytic Leukemia by Cohort and Trimester of Flu Exposure for U5Children, San Francisco Data from Registry System(1969-1973) Ecological Fallacy – Not Sure if women did have Flu!!!
- 11. 11 Population (Correlation) Ecological studies. Advantages • Inexpensive in terms of Time & Money • Routinely available information can be used Limitations • Correlation data represent average exposure levels rather than actual individual levels • Presence of a correlation does not necessarily mean a statistical association. • Exposure cannot be linked with disease.
- 12. Cross-sectional studies- Used for:- •Disease description • Diagnosis and staging of Diseases • Knowing Disease Processes, Mechanisms Research question - “What is happening NOW?” Examples – 1. What is the Prevalence of Hypertension in the population 2. What is the level of Patient Satisfaction in Govt vs Pvt hospitals
- 14. Cross sectional study With outcome Without outcome Time No direction of enquiry Question is – ‘what is happening?’ Population having many exposures and Outcomes
- 15. Fairly quick to perform Less Expensive
- 16. Not very Useful to study disease Etiology
- 17. Case–Control Studies (Pt. Profile) • A 55 yr old women was in excellent health 2 wks before admission, when she developed malaise, low-grade fever, cough and generalized muscle pain. • Although she took aspirin, her symptoms became worse in next few days; particularly muscle pain, which incapacitated her. • Her history was unremarkable except for insomnia, for which she took self prescribed L-tryptophan.
- 18. Patient profile Ctd….. •On physical examination, she had mild, diffuse muscle tenderness and a mild, erythematous maculopapular rash over much of her body. •Laboratory results – elevated eosinophil count 2000 cells per mm3. •Diagnosed Eosinophil-Myalgia Syndrome (EMS). •Nation wide surveillance identified 1500 cases, including 40 fatalities between mid 1988 to end of 1989.
- 19. Ctd…. • Case control studies established strong association of ingesting L-tryptopan and EMS. • After recall of L-tryptophan from market reported cases fell to near zero. • Nearly everyone with EMS and less than 50% without it consumed L-tryptopan produced by one particular manufacturer. • Risk of getting EMS after consuming L-tryptopan of this manufacturer was 20-40 times more than the risk among those who took L-tryptopan of other manufacturers.
- 20. Case–Control Study Cases EMS Control No EMS OnsetDirection of enquiry Time Consumed L-tryptophan Did not Consumed L-tryptophan Question is – ‘what happened?’ Consumed L-tryptophan Did not Consumed L-tryptophan OutcomeExposure
- 21. Case–Control Study • Efficient design to study rare diseases like EMS, Reye’s Syndrome • Fewer subjects are required hence more feasible and cost effective • Allows researchers to investigate many risk factors (Exposures) • Does not prove causality but provide evidence for a causal relationship that warrant public health action
- 22. Case Control Study Population based Hospital based Source population is better defined Subjects are more accessible Easier to make sure that both cases and controls arise from same source population Subjects tend to be more co-operative Exposure history of controls are more likely to reflect people without the disease in the population Easier to collect exposure information from hospital records
- 23. Important Steps in Case Control Studies 1. Selection of Cases and Controls 2. Matching of Cases and Controls 3. Determination of exposure 4. Analysis e.g. Require appropriate matched analysis
- 24. 1. Selection of Cases and Controls: Case selection Criteria should be Selection as a Case or Control Must depend on Outcome and not on exposure history – Both Cases and Controls should be Selected from a well defined source population for better generalization of results – Controls should have same levels of exposure as the unaffected person in the source population. –Bias - Selection Bias (knowledge of association)! Error in Control selection, Low participation!! – Incident cases are preferred over prevalent cases to for making inference about association between risk factor and developing the disease
- 25. Caution… • When difference in exposure is observed btw cases and controls, always ask – whether the level of exposure observed in controls is really the level expected in the population or whether – perhaps due to the manner of selection – the controls may have particularly high or low level of exposure than in the study population!!!!!!!! • Mac Mohan et al – case-control study for association of Coffee with pancreatic Ca 1974-79!
- 26. 2. Matching is done to avoid confounding; BUT – Require appropriate matched analysis – Continuous variable like age require forming of categories e.g. 5 yr groups (Matching a 17 yr old Jain NRI boy with any Jain NRI boy of 15 to 20 yr!!) – Matching increases the statistical efficiency of case – control comparisons. A particular level of power of study is achieved with smaller sample size; hence good for rare diseases – We can select cases and control in the ratio of 1:4 to enhance the power of the study Matching is time consuming hence costly and any variable that is matched cannot be evaluated as RF
- 27. 3. Determination of exposure: as accurate as possible for Risk factor as well as Other Exposures; for each individual. • Information concerning other exposures is used to rule out any spurious association • Slowly developing diseases lack early evidence of involvement – hence establishing temporal sequence of exposure and development of disease is almost impossible. –Interview or questionnaires are used to collect information (recall bias) –Biomarkers can be an objective mean of information
- 28. 4. Analysis of case-control study - Unmatched Design Exposed Unexposed Total Cases A B A+B Control C D C+D Total A+C B+D A+B+C+D Case exposure probability = Exposed cases All cases A A+B = Odds of Case exposure = Exposed cases All cases Unexposed cases All cases A A+B = B A+B A B = Odds of Control exposure = C D Odds Ratio = A B C D = AXD CXB
- 29. Analysis of case-control study - Unmatched Design Used Lot A Used Other Lots Total Cases 22 (A) 36 (B) 58 Control 7 (C) 86 (D) 93 Total 29 122 151 Odds Ratio = AXD CXB = 22 X 86 36 X 7 = 1892 252 = 7.5 95% CI of OR is 2.9 – 19.1 Statistically Significant (Null value of OR = 1, is well outside 95% CI) When incident cases and controls are sampled from the same source population, the exposure OR provides a valid estimate Of Relative Risk
- 30. Analysis of matched design • One control is matched to Each Case • Each case-control pair can be classified into one the following combination:- A-Both case and control is exposed - Concordant Pair B-Case exposed but control is unexposed C-Case unexposed but control exposed D-Both case and control unexposed - Concordant Pair Discordant Pair OR = B C Control Exposed Control Unexposed Total Cases exposed 132 (A) 57 (B) 189 Case unexposed 05 (C) 06 (D) 11 Total 137 63 200 57 05 95% CI = 04.6 to 28.3 = = 11.4
- 31. Standard Normal Curve Area = 1 Mean=Mode=Median = 0 2.28% 2.28% Standard Z Score= x-/ Calculate area under Curve Using Z Table
- 32. Standard Z Score= x-/ • Calculate area under Normal Curve Using Z Table Example - in a Normotensive Pop. Av. BP is 110 mmHg () • If = 4 mmHg • Then what a man having BP as 118 mmHg is Normotensive or Hypertensive? • Z= x-/, = 2.0 • Area under Normal Curve at Z Score 2.0 = .9772 • Then chance of this man with 118 mmHg BP being Normotensive are 97.72% and being Hypertensive are 100- 97.72= 2.28%
- 34. Power = 1- Population 1 Population 2 FP FN
- 35. SE = /n 95% CI
- 37. The confidence interval around the odds ratio • An approximate 95% CI around the point estimate of the odds ratio (OR) for an un matched case-control study • 95% CI = (OR)exp ± 1.96 • = (7.5)exp ± 1.96 • =(7.5)exp ± 1.96 • =(7.5)exp ± 1.96 0.225 • =(7.5)exp (±0.93) i.e. 95% CI = 2.9 TO 19.1 1/A + 1/B + 1/C + 1/D 1/22 + 1/36 + 1/7+ 1/86 0.045 + 0.03 + 0.141+ 0.01
- 39. OR as an estimator of the IRR • Source population from which cases are coming is basically a cohort in which all persons were disease free at the start; P are exposed and Q not exposed. If this cohort is followed for t years A of the P exposed and B of the Q unexposed subjects develop disease • To calculate IR for this cohort we need person years of observation (py) • (py) = Av. Size of source population X length of follow up (if there are no major changes in Pop.) • i.e. there are P X t and Q X t, py of observation in exposed and unexposed groups
- 40. • IRR = (A/Pxt) / (B/Qxt) = (A X Q) / (B X P) = AXP/BXQ • If only incident cases from Dis. persons and control from non-Dis. persons are selected • without regard to exposure - the proportion of cases that are exposed should, on average, equal the proportion of cases in the full cohort. • Thus, the exposure odds a/b among cases, is an estimate of A/B, the corresponding odds among new cases arising from the full cohort. Similarly c/d is an estimate of P/Q • i.e. OR (aXd) / (bXc) is an estimate of AXP/BXQ
- 41. Advantages and Disadvantages of Case-Control Studies • Efficient for the study of rare diseases • Efficient for the study of Chronic diseases • Tend to require smaller Sample Size • Less Expensive • May be completed in less time • Risk of disease can not be calculated directly • Not efficient for rare Exposures • More susceptible for selection and recall bias • Information on exposure may be less accurate
- 42. Questions A case Control Study id characterized by all of the following except: 1. It is less expensive 2. Patients with the disease are compared with persons without the disease 3. Incidence Rates can be computed directly 4. Assessment of pst exposure may be biased 5. Definition of cases may be difficult
- 43. Which of the following is a case control study: 1. Study of past mortality trends to permit estimates of the occurrence of disease in future 2. Analysis of previous research in different places & under different circumstances to permit the establishment of hypothesis based on cumulative knowledge of all known factors 3. Obtaining information from a known disease group and from a comparison group not having this disease to determine the relative frequency of the exposure in diseased
- 44. Ecologic fallacy refer to: 1. Assessing exposure in large groups rather than in many small groups 2. Assessing outcome in large groups rather than in many small groups 3. Ascribing characteristic of a large group to every individual of that group 4. Failure to examine temporal relationship between exposure and outcome
- 45. In which of the following types of study design does a subject serve as his own control: 1. Prospective cohort study 2. Retrospective cohort study 3. Case crossover study 4. Case control study
Editor's Notes
- Limitations Exposure cannot be linked with disease as whole population is represented. Presence of a correlation does not necessarily mean a statistical association. Correlation data represent average exposure levels rather than actual individual levels
- analyze data collected on a group of subjects at one time rather than over a period of time. Cross-sectional studies are designed to determine “What is happening?” right now. Subjects are selected and information is obtained in a short period of time Because they focus on a point in time, they are sometimes also called prevalence studies. Surveys and polls are generally cross-sectional studies, although surveys can be part of a cohort or case–control study. Cross-sectional studies may be designed to address research questions raised by a case–series, or they may be done without a previous descriptive study. Subjects are selected and information is obtained in a short period of time Because they focus on a point in time, they are sometimes also called prevalence studies.
- In early 1940s, Alton Oschner, a surgeon in New Orleans, observed that virtually all of the lung Ca patients which he has operated were smokers. Although this relationship is established now but at that time it was controversial! He hupothesised that smoking is linked with lung cancer- was this valid? Again in 1940s, Sir Norman Gregg, an Australian Ophthalmologist, observed that a number of infants and young children presenting with unusual form of cataract have been in utero at the time of rubella outbreak!!! – he hypothesized that there is an association (that time it was not known that virus is teratogenic!!!!)
- In November 1989 CDC Atlanta and local health departments published the first description of EMS – characterized by incapacitating myalgias, elevated eosinophil counts, and in some patients arthralgias, hair loss, skin thickening and interstitial lung disease. L-tryptophan is an essential amino acid available without prescription EMS occur predominantly in women and is relatively rare. Nation wide surveillance identified 1500 cases, including 40 fatalities. Nearly all cases occurred btw mid 1988- to end of 1989. case control studies established strong association of ingesting L-tryptopan and EMS. After recall of L-tryptophan from market reported cases fell to near zero. Case control studies showed that nearly everyone with EMS and less than 50% without it consumed L-tryptopan produced by one particular manufacturer. Risk of getting EMS after consuming L-tryptopan of this manufacturer was 20-40 times more than the risk among those who took L-tryptopan of other manufacturers. There were many contaminants but exact one couldn’t be found bcz of ethical issues- no animal testing! Astute (judicious) observations and quick public health response led to timely recall of L-tryptopan and prevented larger outbreak.
- Case–control studies begin with the absence or presence of an outcome and then look backward in time to try to detect possible causes or risk factors (Exposure) that may have been suggested in a case–series report. The cases in case–control studies are individuals selected on the basis of some disease or outcome; the controls are individuals without the disease or outcome. The history or previous events of both cases and controls are analyzed in an attempt to identify a characteristic or risk factor present in the cases' histories but not in the controls' histories. Figure illustrates that subjects in the study are chosen at the onset of the study after they are known to be either cases with the disease or outcome or controls without the disease or outcome. The histories of cases and controls are examined over a previous period to detect the presence (shaded areas) or absence (unshaded areas) of predisposing characteristics or risk factors, or, if the disease is infectious, whether the subject has been exposed to the presumed infectious agent. In case–control designs, the nature of the inquiry is backward in time, as indicated by the arrows pointing backward to illustrate the backward, or retrospective, nature of the research process. We can characterize case–control studies as studies that ask “What happened?” In fact, they are sometimes called retrospective studies because of the direction of inquiry. Case–control studies are longitudinal as well, because the inquiry covers a period of time. Investigators sometimes use matching to associate controls with cases on characteristics such as age and sex. If an investigator feels that such characteristics are so important that an imbalance between the two groups of patients would affect any conclusions, he or she should employ matching. This process ensures that both groups will be similar with respect to important characteristics that may otherwise cloud or confound the conclusions. Deciding whether a published study is a case–control study or a case–series report is not always easy. Confusion arises because both types of studies are generally conceived and written after the fact rather than having been planned. The easiest way to differentiate between them is to ask whether the author's purpose was to describe a phenomenon or to attempt to explain it by evaluating previous events. If the purpose is simple description, chances are the study is a case–series report.
- Population based case control studies select newly diagnosed cases and controls from a well defined population Hospital base case control studies usually use prevalent rather than incident cases and take controls from conveniently available patients of other diseases, in the same institution. Ex.- case control study of Reye’s Syndrome (a condition characterized by encephalopathy associated with fatty degeneration of liver, occurs almost exclusively in children and typically follows a viral illness). Cases were selected from children admitted with Reye’s Syndrome in any hospital of the city and controls from same institution from children admitted with some other illness preferably viral, to find out any association btw any exposure (here – aspirin intake) and Reye’s syn. 26 out of 27 cases and only 6 out of 22 control took aspirin. In hospital based study patients are more willing to participate. Factors like SES are balanced as both cases and control are from same hospital BUT… distortion arise as source population is not defined moreover controls are patients suffering from other diseases which may confound the results (if exposure history of controls differ from unaffected people in the population). To rule out this select controls from various diagnostic groups and early acute conditions so that earlier exposures are not affected by dis condition. Also donot select pts with multiple conditions and controls with condition related to the disease of interest
- Case definition – e.g. lung cancer confirmed by biopsy • Prevalent vs. incident cases Prevalent: • No need for waiting • RFs may be more related to survival than incidence. If many people die soon after diagnosis, may over-represent long term survivors Incident: • Recruit new cases at time of disease occurrence • Better for making inference about association between risk factor and developing the disease Controls should have same levels of exposure as the unaffected person in the source population. Should be comparable to cases. • Should have the potential to become cases (must be susceptible to the disease of interest) • Possible control sources: population, neighborhood, friend, hospital knowing! - Publicity of concerning the suspected association, Low participation – if exposure histories are differrent in participants and non participants, error in selecting controls- e.g. pts of insomnia (more chance of taking L-tryptophan) In 1929 Raymond Pearl, professor of biostatistics at John Hopkins conducted a study to test if TB is protective for Cancer – from 7500 consecutive autopsies he identified 816 cancer cases and selected 816 other autopsies randomly and determined proportion of TB in cases and controls – 6.6% vs 16.3% (since it was less in cases he concluded that TB had antagonistic or protective effect). Was it justified? – only if proportion of TB in non-cancer patients is same as it was in controls. Which was not the case!!! actually at those times TB was quite prevalent and he selected controls from other patients other than cancer admitted and died in the hospital during that time. And many died due to TB Carlsons and Bell repeated Pearl’s study – compared pts who died of cancer to pts who died of heart disease. They found no difference!!!
- Controls were cases of disease other than cancer pancreas admitted by same gastroenterologist - usually of esophagitis and peptic ulcer (they are prone to consume less coffee)
- 15 to 20 yr!! May be too broad to loose relevance to any comparision
- To remove recall bias other methods should be employed to verify – e.g. see drug packages in case of L-tryptophan use (manufacture could also be verified) Medical record, occupational records, etc Biomarkers though objective but are costly, invasive and not always available
- 118-110= 8, z = 8/ 4= 2.0 Area under normal curve at z score 2.0 = at z table at x axis 2.0 and on y axis 0.0 = 0.9772 if we multiply it with 100 it is 97.72% i.e. only 2.3% (100-97.72 = 2.3) chance is that this person having BP od 118 mm of Hg is not from the same population having average BP as 110 mm of Hg (normotensive)
- Now, turning to the case-control study design, cases arise from a clearly defined source population and the investigator then chooses controls from this same population. Thus to conduct a case control study - cases i.e. diseased persons- incident cases only are taken. Both cases and controls are selected without regard to exposure so that proportion of cases in the study that are exposed should, on average, equal the proportion of cases in the full cohort.