HSS4303B – Intro To Epidemiology Interpretation of epidemiologic literature

1. HSS4303B – Intro To Epidemiology Interpretation of epidemiologic literature Prof R Deonandan ray@deonandan.com

2. Submission Due Date – January 26th, 2011. Please see www.IJHS.ca for submission criteria Visitez www.RISS.ca pour des CritèresDe Soumission La date limite de soumission est le 26 janvier.

3. Dr Gomes?

4. Consider This Scenario • A 40-year-old accountant visited her family physician for a routine checkup. The patient's mother had been diagnosed with breast cancer in the past year, and the patient wanted advice about what she could do to reduce her own risk of developing this disease. The patient had two children aged 6 and 8 years. She was in good health, with regular menstrual cycles, and she had a recent normal Papanicolaou smear and mammogram.

5. In responding to the patient's questions about breast cancer, the physician confirmed that a positive family history increases the risk of developing this disease.

6. A number of other characteristics are associated with a reduced risk of developing breast cancer, such as early age at first full-term pregnancy and increasing number of pregnancies. Unfortunately, these factors are not easily susceptible to intervention, and the patient already had completed her childbearing.

7. The physician was also aware of a controversy regarding the relationship between the intake of dietary fat and the occurrence of breast cancer

8. So what advice should the doctor give? Before recommending that the patient reduce her fat intake, however, the physician wished to review the pertinent medical literature

9. Evidence Based Medicine (EBM)

10. What is EBM? • “Evidence Based Medicine (EBM) is the integration of best research evidence with clinical expertise and patient values.” • -Sackett, et al • It’s a way to use the literature to help you make clinical decisions in a systematic fashion • Common sense? • Ideology?

11. What is “best research evidence”?  Clinically relevant research, often from the basic sciences but typically from medical literature. What is “clinical expertise”?  The ability to use your clinical skills and past experience to rapidly identify each patient’s unique health state and diagnosis, individual risks and benefits of potential intervention, and their personal values and expectations. What are “patient values”?  The unique preferences, concerns and expectations each patient brings to a clinical encounter and which must be integrated into clinical decisions if they are to serve the patient.

12. Why the sudden interest in EBM?  EBM has been around since post-revolutionary Paris. But recent interest has been spurred by 4 realizations: • Doctors need daily information about diagnosis, prognosis, therapy and prevention • Textbooks are often out of date; experts are often wrong; CMEs are often useless; and there are too many journal articles • Clinicians’ technical knowledge declines over time • Only a few seconds can be afforded per patient for assimilating a mountain of evidence, and only 30 min per week can be set aside for general reading

13. Recent developments have made EBM possible: • Strategies for efficiently finding and appraising evidence • Systematic reviews and concise summaries of ongoing research • Evidence-based journals (that publish the 2% of clinical articles that are both valid and of immediate clinical use) • New information systems (i.e., computers) • New attitudes toward lifelong learning and professional development

14. Why Is EBM So Popular? • Purports to employ the vast body of medical research that has been accumulating over the past few decades for direct clinical application • In theory, it’s cheaper

15. How does one actually practice EBM? Five Steps: • Convert the need for information (about prevention, diagnosis, prognosis, therapy, causation, etc) into an answerable question • Track down the best evidence with which to answer that question • Critically appraise that evidence for its validity (closeness to the truth), impact (size of the effect) and applicability (usefulness) • Integrate the evidence with your clinical expertise, experience and the patient’s unique biology, circumstances and values… and discuss with patient to make joint decision • Evaluate your effectiveness and efficiency in doing steps 1-4 so that they can be improved next time

16. Are there alternatives to EBM? (From Isaacs & Fitzgerald (1999). BMJ:319:pp1618-1619) 1. Eminence based medicine - The more senior the colleague, the less importance he places on the need for anything as mundane as evidence. Experience, it seems, is worth any amount of evidence. Experience is "making the same mistakes with increasing confidence over an impressive number of years.“ 2. Vehemence based medicine - The substitution of volume for evidence is an effective technique for brow beating your more timorous colleagues. 3. Eloquence based medicine - Elegance and eloquence are powerful substitutes for evidence. 4. Providence based medicine - If the doctor has no idea of what to do next, the decision may be best left in the hands of the Almighty. 5. Nervousness based medicine - Fear of litigation is a powerful stimulus for overinvestigation and overtreatment. 6. Confidence based medicine - This is restricted to surgeons

17. Types of Relevant Literature • Peer-reviewed journal studies • Meta-analyses • Systematic reviews

18. Must find “current best” evidence… Last year’s “best” may not be this year’s “best”. • From Sackett, et al: • Burn your textbooks. • “We begin with textbooks only to dismiss them.” •  Textbooks are good for the pathophysiology of a clinical problem, but not for establishing cause, diagnosis, prognosis, prevention or treatment. Trust only those that are revised once a year and that are referenced. • 2. Rely on clinical databases (most of which are now electronic). Online journals, like Evidence-Base Medicine • (Sackett is a bit extreme.)

19. The best sources for pre-approved evidence-based studies –if you can get access to them-- are the Cochrane Collaboration Library and any number of EBM online journals, such as Best Evidence • Cochrane Library:update.cochrane.co.uk or www.updateusa.com • -provides systematic reviews of trials of health care interventions • 2. Best Evidence: www.acponline.com • -summarizes individual studies and systematic reviews from over 100 medical journals • 3. Aidsline • -like Medline, but for AIDS studies • 4. Evidence Based Medicine Reviews (EBMR): www.ovid.com • -combines many electronic databases, such as Cochrane, Medline, Cancerlit and Aidsline

20. RCT – groups of patients are randomized into either experiment or control groups Cohort – following exposed and unexposed patients forward to determine outcome Case Control – looking at patients with the outcome of interest and looking back to see if they had the exposure in question Case Series – a report on a series of patients with an outcome of interest; no control group involved Systematic Review – a summary of the literature that uses explicit methods to appraise and combine studies Meta Analyses – A systematic review that uses quantitative methods to summarize the results

21. Literature search question • Formulate research ____________ • State your hypothesis or ask your question • Define the ___________ of the study • Steps to find an answer to the research question • Develop a search _________ • Identify key words, scope and limitation of the search • Conduct literature ________ • Identify databases, search criteria • Search the databases both electronically and manually • Create your database of the identified literature • Read the collected literature scope strategy search

22. Reading of the collected literature • Read the paper and collect information on: • Research question or hypothesis • Study design • Selection of cases and controls • Outcome and predictor variables • Method of analyses • Sources of bias • Interpretation of results • Group studies by type of study design and type of reporting • Prepare study summaries • Summarize the findings in a tabular format

23. Stepwise Approach to Critical Appraisal of Published Medical Research.

25. So remember our example? • The doctor wants to research the effects of dietary fat on breast cancer risk

26. Asking Research Question • The PICO model: • Patient Population - Who are your patient and his/her cohorts? Intervention - What action are you considering? Comparison - What are the alternatives? Outcomes - What do you expect to accomplish? • What type of question do you want to ask? • Therapy - What treatment and outcomes? Diagnosis - Should I perform this test? Prognosis - What is the outlook for the patient? Harm - What is the relationship between a disease and a possible cause?

27. A Well Built Clinical Question Another Example: A new patient presents with mid upper right abdominal pain. She is a 47 year old white woman without any significant past medical history. She is nauseous but has not vomited. She reports no change in her bowel movements and has not eaten anything out of the ordinary today. On physical examination she is very tender in her mid and right upper abdominal region. Lab tests and abdominal x-rays are ordered. The patient is given over-the-counter antacids. If the pain is not relieved soon, you are considering offering prescription pain control drugs, such as codeine or morphine. But you are worried that the administration of opioid analgesics will interfere with your ability to diagnose the problem….

28. The appropriate question might be: PATIENT POPULATION: patients with acute abdominal pain INTERVENTION: narcotics COMPARISON: (none) OUTCOME: do narcotics affect the diagnosis? Type of Question: Diagnosis or Therapy Type of Study: Randomized Controlled Trial. “In patients with acute abdominal pain does the use of narcotics affect the diagnosis of the problem?”

29. What about our dietary fat and breast cancer question?

30. The appropriate question might be: PATIENT POPULATION: adult women INTERVENTION: dietary fat COMPARISON: (none) OUTCOME: breast cancer? Type of Question: Etiologic Type of Study: Any “In adult women, is dietary fat a risk factor for breast cancer?”

33. What Does “Significant” Mean? • Significance of the reported finding in the context of our research question • statistically significant • biologically plausible • causal association between exposure and disease development • significance of biological markers used in the study • relevance to the population of interest Types of Significance in Clinical Research.

34. Study design considerations • The appropriateness of the study design to the research question should be assessed. • The incidence rate of the disease in question may be a determining factor. • Although breast cancer is the most common form of cancer among women in the United States, this disease is diagnosed among only a small proportion of women during a short period of time. • Accordingly, a case–control study would offer an efficient approach to studying this disease, since the sampling scheme for this type of study identifies affected women once they are diagnosed. • In fact, studies of dietary fat intake and occurrence of breast cancer have utilized several different designs, including descriptive, case–control, and cohort studies. • The descriptive studies are useful for hypothesis generation, but not for hypothesis testing. • The case–control and cohort designs provide more compelling evidence to test specific hypotheses. • To date, all of the published studies of dietary fat and risk of developing breast cancer in humans have employed observational designs.

35. “Hierarchy of Evidence” [Source: Source: SUNY Downstate Medical Center. Medical Research Library of Brooklyn. Evidence Based Medicine Course. A Guide to Research Methods: The Evidence Pyramid: http://servers.medlib.hscbklyn.edu/ebm/2100.htm]

36. Outcome variables • In investigations of the relationship between dietary fat intake and risk of developing breast cancer, it is important to specify how the presence or absence of breast cancer was determined. There are several possibilities. • Death certificates limit information to deceased subjects. In addition, a variety of studies have shown that information on death certificates may be incomplete or inaccurate • Self-reports require that subjects be alive or have relatives who can provide information on breast cancer. If the subjects are not medically sophisticated, they may mistake benign forms of breast disease for breast cancer. • Medical records may provide more accurate information. However, it is possible that diagnostic criteria differ from physician to physician, over time, or across geographic regions or countries. • Histopathologic diagnoses provide the most definitive information, but adequate tissue must be available for pathologic examination.

37. Predictor variables (1) Primary explanatory variable? • The _________________ is the risk factor or exposure under investigation. • Studies may involve a single risk factor of interest or several different predictor variables. If a number of exposure variables are included, they may or may not be closely linked. • In a study of the cause of breast cancer, an investigator might choose to examine a variety of exposure variables, including reproductive factors such as age at first full-term pregnancy, hormone levels, exposure to radiation, and dietary fat intake. • Although this sort of study may provide a more comprehensive picture of the causes of breast cancer, it may limit the ability to collect detailed information on each exposure of interest.

38. Predictor variables (2) • Even if a study is focused on the question of dietary fat and the risk of developing breast cancer, it is necessary to collect some basic information on other possible determinants of breast cancer that could act as confounders. • _________________ are important because they can provide quantitative documentation of exposure in certain circumstances. • No biological markers of fat intake are currently available, but to assess long-term intake of dietary fat, the fatty acid content of adipose tissue could be measured in biopsies. • Obviously, the utility of such a measure depends on the extent to which it accurately reflects consumption patterns. Covariates?

39. Method of analysis • The type of statistical test that should be used is determined by: • The goal of the analysis (eg, to compare groups, to explore an association, or to predict an outcome) and • The types of variables used in the analysis (eg, categorical, ordinal, or continuous variables). • By convention, the 5% level of statistical significance is used as a standard in many biomedical studies. That is, the investigator is willing to accept a 1 in 20 risk that the observed effect is a result of chance variation alone. • 1% or smaller are also quite common (p<0.01) • However, care must be taken to avoid over-simplistic interpretations of p values. (p<0.05) • One common mistake is to assume that a statistically significant result is biologically or clinically important (p<0.05). • Clinical importance and biological plausibility of results are not assessed by hypothesis tests.

40. Possible sources of bias Biases can occur in any study, although certain study designs are more susceptible to biases than others Potential biases cannot be assessed in precise quantitative terms but can be reduced or even eliminated through proper study design considerations

41. Possible sources of bias Biases can occur in any study, although certain study designs are more susceptible to biases than others Potential biases cannot be assessed in precise quantitative terms but can be reduced or even eliminated through proper study design considerations

42. Possible sources of bias Biases can occur in any study, although certain study designs are more susceptible to biases than others Potential biases cannot be assessed in precise quantitative terms but can be reduced or even eliminated through proper study design considerations

43. Possible sources of bias Biases can occur in any study, although certain study designs are more susceptible to biases than others Potential biases cannot be assessed in precise quantitative terms but can be reduced or even eliminated through proper study design considerations

44. Selection Bias • If a paper describes a study of 20 women who ate a variety of fatty foods to see which ones got breast cancer • Turns out they selected the 20 women from a small town of 200 people whose families had been there for centuries • Where is the bias?

45. Misclassification bias • A case-control study tries to relate dietary fat to breast cancer by looking at death certificates (for cause of death) and comparing them to family-reported dietary activities • 50 cases of women who did not die of breast cancer were compared to 50 cases of women who did • But breast cancer may not have been primary cause of death in many cases • Some controls may have been misclassified as non-breast cancer patients

46. Confounding Bias • What is confounding? • A variable that masks an association between an exposure and an outcome –or that creates a false association

47. Confounding Smoking Confounder Exposure Outcome Shop class/ Breathing English class problems

48. Classic Confounders Age Sex Socioeconomic status Smoking status That’s why, often analyses are stratified by these variables

49. Confounding Sex Confounder Exposure Outcome Nursing students/ Pregnancy Engineering students

50. Confounding A confounder is not in the causal pathway Example: Exposure: diet Outcome: heart disease cholesterol