Goldsmith’s teachers lecture 2011 Medical statistics Joan Morris Professor of Medical Statistics

1. Goldsmith’s teachers lecture 2011 Medical statistics Joan Morris Professor of Medical Statistics

2. To describe medical statistics To give examples of where medical statistics has contributed to society Use of statistics in screening To mention some novel statistical methods Aims

3. Statistics is a mathematical science pertaining to the collection, analysis, interpretation or explanation, and presentation of data. Statistics - definition

4. Data Collection

5. Florence Nightingale She realised that soldiers were dying from malnutrition, poor sanitation, and lack of activity. She kept meticulous records of the death toll in the hospitals as evidence of the importance of patient welfare. Data Collection

6. Polar Area Diagrams

7. National Mortality Statistics Health survey for England and Wales Population statistics ….. Large amounts of data are available on the web National Data Collection

9. Standardised mortality ratios: Mortality from skin cancer

10. All births in England and Wales according to maternal age :1989-91 compared with 2005-2007 2005-07 : 1991,000 births 1989-91 : 2090,000 births

11. Comparisons of individuals Observational cross-sectionalcase-control studiescohort studies InterventionalRandomised controlled trials Comparisons of populations Time trends Ecological studies:Geographical variationsAge/sex patternsSocial variations Epidemiology Epidemiology

12. Study Design Ensure “valid” data is collected Ensure enough data is collected Main designs Case control studies Cohort studies Clinical trials Comparison of Individuals

13. Richard Doll (doctor) and Austin Bradford Hill (statistician)

14. British Doctors Cohort Study (BMJ 1994;309:901-911) 34,000 British male doctors who replied to a postal questionnaire in 1951 and further questionnaires in 1957, 66, 72, 78, 90, … Flagged the doctors at NHSCR and obtained their death certificates as they died. Compared death rates in smokers and non-smokers.. Is there a relationship between smoking and lung cancer?

15. Is there a relationship between smoking and lung cancer?

16. Sudden Infant Death Syndrome Case Control Study Methods Collected information about infants that were potential “SIDS” Identified “similar” children who had not died Compared the differences Results Children who died were much more likely to have been put on their fronts to sleep than children who did not die What causes Sudden Infant Death Syndrome ?

18. A clinical trial is an experiment in which a treatment is administered to humans in order to evaluate its efficacy and safety Randomised = allocated to groups on basis of chance e.g. tossing a coin (ensures fair comparison) Controlled = a comparison group Randomised Controlled Trial

19. MRC Vitamin trial - randomised controlled trial Large: 1817 women who had had a previous NTD, 33 centres, 7 countries Can folic acid reduce neural tube defects (e.g. spina bifida)?

20. Results : Women who did not receive folic acid were 3 times more likely to have a second NTD pregnancy Impact : Women are advised to take folic acid prior to becoming pregnant Majority of countries around the world fortify flour with folic acid Can folic acid reduce neural tube defects (e.g. spina bifida)?

22. Study Design Cohort Case Control Clinical Trial Collection of Data

23. Could the observed results have arisen by chance ? Given that we have a sample what can we say about the population from which the sample comes Analysis

24. Neural Tube Defects Yes No Total Folic Acid Yes 6 587 593 No 21 581 602 Folic Acid vs Placebo forNeural Tube Defects Risk of NTD in treated group = Risk of NTD in control group = Relative Risk of NTD in treated group compared to control group =

25. P is the probability of the observed event or one more extreme occurring if the null hypothesis is true Null hypothesis : No difference in treatments P = probability out of 27 babies with an NTD what is the chance that 6 or less are in the FA group and 21 in placebo group IF FA has no effect P values

26. Interpreting the results of a trial RR death in A vs B = 2.0 Is it due to chance or not ?

27. P < 0.05 is taken to mean statistical significance This means if there is no difference between treatments, and you do 20 trials one will be statistically significant P values

28. Folic Acid vs Placebo forNeural Tube Defects RR = 0.29 P = 0.008 Therefore we assume there is a real difference between the folic acid group and the placebo group But how big is the reduction ?

29. Folic Acid vs Placebo forNeural Tube Defects RR = 0.29 P = 0.008 95% Confidence Interval : 0.10 to 0.76 95% confidence intervals means that 95% of the time this interval contains the true reduction Therefore it gives an indication of the likely size of the reduction

30. Folic Acid and NTD Dose Response

31. Folic Acid and NTD Dose Response

32. The same proportional increase in serum folate has the same proportional reduction in NTD All women benefit from taking folic acid. There is not a threshold effect Interpretation

33. Collection Nightingale National statistics Study design Presentation Estimates and confidence intervals Analysis Vital to interpretation So far….

34. Use of Statistics in Screening Screening is the identification, among apparently healthy individuals, of those who are sufficiently at risk from a specific disorder to benefit from a subsequent diagnostic test, procedure or direct preventive action. Screening for Heart Disease

35. Relative odds of major IHD event by fifths of the distribution of haemostatic and lipid markers for all men (•——•) and for men free of IHD at baseline examination (∘–––∘). Yarnell J et al. Eur Heart J 2004;25:1049-1056 The European Society of Cardiology

36. Unaffected Affected Biomarker : ZZ

37. Unaffected Affected Biomarker : ZZ Screen positive Screen negative

38. False negatives False positives Biomarker : ZZ Screen positive Screen negative

39. Screening for a medical disorder Good test Affected Unaffected Risk Factor

40. Screening for a medical disorder Poor test Affected Unaffected Risk Factor

41. Unaffected Affected Is Cholesterol any good for screening ? Risk screen converter www.wolfson.qmul.ac.uk/rsc/

42. Detection Rate False Positive Rate

43. 4.2mm Hg

44. 7.5mm Hg

46. Are there any good screening tests ? Antenatal screening for Down’s syndrome

47. Quadruple test markers AFP uE3 Unaffected Down’s syndrome Unaffected Down’s syndrome Total hCG Inhibin-A Unaffected Unaffected Down’s syndrome Down’s syndrome

48. Distribution of risk in Down’s syndrome and unaffected pregnancies using AFP, uE3, total hCG and inhibin-A measured at 14-20 weeks (+ maternal age) Unaffected Down’s syndrome 1:108 1:106 1:104 1:102 1:1 102:1 104:1 Risk of a Down’s syndrome pregnancy at term

49. Collection Analysis Interpretation or explanation Presentation Recent Developments

50. Danish mother and child study Recruiting people on the internet Linking data sets Probability linking eg Date of mother’s birth fairly accurate Gestational age of baby often wrong Weight of baby –REALLY ACCURATE !!! Collection