1. Medical Statistics: Users’ Manual Arash Etemadi, MD PhD Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences aetemadi@tums.ac.ir

2. Why does good evidence from research fail to get into practice?? - 75% cannot understand the statistics - 70% cannot critically appraise a research paper Using Research for Practice: A UK Experience of the barriers scale Dunn V, Crichton C, Williams K, Roe B, Seers K

4. Do we have to build the car we drive?

5. Why is statistics necessary? –58% of the population had GERD –Mean age of the respondents was 25+8 –25% of women and 50% of men lied about their age –Doctors live longer than normal people. (4 in each group!?)

6. Why is statistics necessary? Descriptive statistics –58% of the population had GERD –Mean age of the respondents was 25+8 Inferential statistics –25% of women and 50% of men lied about their age –Doctors live longer than normal people. (4 in each group!?)

7. Descriptive statistics Point estimates: Mean, median, mode, relative frequency Distribution: Standard deviation

8. Inferential statistics: exploring associations and differences

9. Differences Continuous variables (blood pressure, age): 109+11 vs. 140+10 Categorical variables (proportion of blind people): 10% vs. 2%

10. Measures of Association Relative Risk (RR) Odds Ratio (OR) Absolute risk reduction Relative risk reduction Number needed to treat Treatment deadaliveTotal Medical 4049211325 CABG 3509741324

11. Number Needed to Treat (NNT) (very trendy but tricky): only defined for a specific intervention! only defined for a specific outcome! – eg. Pravastatin™ 40 mg nocte x10 years, in a 65 year old male, ex-smoker with high BP and Diabetes, to reduce MI or Death. NNT is the inverse of Absolute Risk Reduction: i.e. NNT = 1/ARR

12. Measures of Association Linear Correlation –Conditions –r and p, CI Regression –Univariate –Multiple Regression –Logistic Regression –Cox Proportional Hazard Model Do they mean causation?

13. Associations may be due to Chance (random error) – statistics are used to reduce it by appropriate design of the study –statistics are used to estimate the probability that the observed results are due to chance Bias (Systematic error) – must be considered in the design of the study Confounding – can be dealt with during both the design and the analysis of the study True association

14. Dealing with chance error During design of study – Sample size – Power During analysis (Statistical measures of chance) – Test of statistical significance (P value) – Confidence intervals

15. Statistical measures of chance I (Test of statistical significance) Association in Reality YesNo Yes No Type I error Type II error Observed association

16. The p-value in a nutshell p < 0.05 a statistically significant result p = 0.05 or 1 in 20 result fairly unlikely to be due to chance 0 1 Could the result have occurred by chance? The result is unlikely to be due to chance The result is likely to be due to chance 1 20 p > 0.05 not a statistically significant result p = 0.5 or 1 in 2 result quite likely to be due to chance 1 2

17. Significantitis Significantitis is the plague of our time. »A. Etemadi, 21 st century epidemiologist The drug reduced blood pressure by 1mmHg (p<0.0000000000000001) Although we showed that half of the newborns could be saved by this method, our results were good-for-nothing (p=0.06)

18. Confidence Interval (CI) Is the range within which the true size of effect (never exactly known) lies, with a given degree of assurance (usually 95%)

19. The ACE inhibitor group had a 5% (95% CI: 1-9) higher survival.

20. Associations may be due to Chance (random error) – statistics are used to reduce it by appropriate design of the study –statistics are used to estimate the probability that the observed results are due to chance Bias (Systematic error) – must be considered in the design of the study Confounding – can be dealt with during both the design and the analysis of the study True association

21. Types of Bias Selection bias – identification of individual subjects for inclusion in study on the basis of either exposure or disease status depends in some way on the other axis of interest Observation (information) bias – results from systematic differences in the way data on exposure or outcome are obtained from the various study groups

22. Associations may be due to Chance (random error) – statistics are used to reduce it by appropriate design of the study –statistics are used to estimate the probability that the observed results are due to chance Bias (Systematic error) – must be considered in the design of the study Confounding – can be dealt with during both the design and the analysis of the study True association

23. Confounding coffee Pancreatic cancer smoking

24. Confounding smokingcoffee Pancreatic cancer

25. Confounding confounder effect Possible cause

26. Associations may be due to Chance (random error) – statistics are used to reduce it by appropriate design of the study –statistics are used to estimate the probability that the observed results are due to chance Bias (Systematic error) – must be considered in the design of the study Confounding – can be dealt with during both the design and the analysis of the study True association

27. 9/3/2015 DETERMINATION OF CAUSATION The general QUESTION: Is there a cause and effect relationship between the presence of factor X and the development of disease Y? One way of determining causation is personal experience by directly observing a sequence of events. How do elevators work?

28. Nature of Evidence: 1. Replication of Findings – –consistent in populations 2. Strength of Association – –significant high risk 3. Temporal Sequence – –exposure precede disease

29. Nature of Evidence: 4. Dose-Response – –higher dose exposure, higher risk 5. Biologic Credibility – –exposure linked to pathogenesis 6. Consideration of alternative explanations – –the extent to which other explanations have been considered.

30. Nature of Evidence 7. Cessation of exposure (Dynamics) – –removal of exposure – reduces risk 8. Specificity –specific exposure is associated with only one disease 9. Experimental evidence

31. H. pylori –Temporal relationship 11% of chronic gastritis patients go on the develop duodenal ulcers over a 10-year period. –Strength H. pylori is found in at least 90% of patients with duodenal ulcer –Dose response density of H.pylori is higher in patients with duodenal ulcer than in patients without –Consistency association has been replicated in other studies

32. H. pylori –Biologic plausibility originally – no biologic plausibility then H. pylori binding sites were found know H. pylori induces inflammation –Specificity prevalence of H. pylori in patients with duodenal ulcers is 90% to 100%

33. First question to ask: Is there any statistics at all? –Is it necessary?

34. Are baseline differences explored and adjusted for? Collins et al. Stat Med; 1987 Nodal status Center 1Center 2 TreatmentControlTreatmentControl 061%64%22%50% 1-328% 31%35% 4+11%7%42%14% N/A01%5%1%

35. What is the appropriate test? –Scales Nominal Ordinal Interval Ratio

36. Normal Distribution

37. Copyright ©1997 BMJ Publishing Group Ltd. Greenhalgh, T. BMJ 1997;315:364-366 Skewed curve

38. Parametric versus non-parametric tests Transformation

39. Jekyl-Frankenestein-Tarkovsky test of variances for unequal modes

40. Subgroup analysis? –Analyses showed that the drug was especially effective in women above 35 who were unable to say supercalifragilisticexpialidocious. –We divided the study population according to sex, then each group were divided to 10 age groups, each age group was subdivided according to educational background and whether they were left-handed or right- handed.

41. Scenario

42. Subgroup analysis

43. Paired analysis?

44. Ten ways to cheat on statistical tests when writing up results Throw all your data into a computer and report as significant any relation where P<0.05 If baseline differences between the groups favour the intervention group, remember not to adjust for them Do not test your data to see if they are normally distributed. If you do, you might get stuck with non- parametric tests, which aren't as much fun Ignore all withdrawals (drop outs) and non- responders, so the analysis only concerns subjects who fully complied with treatment

45. Always assume that you can plot one set of data against another and calculate an "r value" (Pearson correlation coefficient), and assume that a "significant" r value proves causation If outliers (points which lie a long way from the others on your graph) are messing up your calculations, just rub them out. But if outliers are helping your case, even if they seem to be spurious results, leave them in If the confidence intervals of your result overlap zero difference between the groups, leave them out of your report. Better still, mention them briefly in the text but don't draw them in on the graph—and ignore them when drawing your conclusions

46. If the difference between two groups becomes significant four and a half months into a six month trial, stop the trial and start writing up. Alternatively, if at six months the results are "nearly significant," extend the trial for another three weeks If your results prove uninteresting, ask the computer to go back and see if any particular subgroups behaved differently. You might find that your intervention worked after all in Chinese women aged 52-61 If analysing your data the way you plan to does not give the result you wanted, run the figures through a selection of other tests

47. Statistical Tests Type of Data GoalMeasurement (from Gaussian Population) Rank, Score, or Measureme nt (from Non- Gaussian Population) Binomial (Two Possible Outcomes) Survival Time Describe one group Mean, SDMedian, interquartile range ProportionKaplan Meier survival curve Compare one group to a hypothetical value One-sample t testWilcoxon testChi-square or Binomial test ** Compare two unpaired groups Unpaired t testMann-Whitney test Fisher's test (chi-square for large samples) Log-rank test or Mantel- Haenszel* Compare two paired groups Paired t testWilcoxon testMcNemar's testConditional proportional hazards regression*

48. Statistical Tests Compare three or more unmatched groups One-way ANOVAKruskal-Wallis testChi-square testCox proportional hazard regression** Compare three or more matched groups Repeated- measures ANOVA Friedman testCochrane Q**Conditional proportional hazards regression** Quantify association between two variables Pearson correlation Spearman correlation Contingency coefficients** Predict value from another measured variable Simple linear regression or Nonlinear regression Nonparametric regression** Simple logistic regression* Cox proportional hazard regression* Predict value from several measured or binomial variables Multiple linear regression* or Multiple nonlinear regression** Multiple logistic regression* Cox proportional hazard regression*