Medical Statistics Joan Morris (j.k.morris@qmul.ac.uk) Professor of Medical Statistics

1. Medical Statistics Joan Morris (j.k.morris@qmul.ac.uk) Professor of Medical Statistics Goldsmiths Lecture 2014

2. To give a brief description of some different areas of medical statistics Folic acid and Neural Tube Defects Screening for Heart Disease Aims

3. Folic Acid and Neural Tube Defects

4. MRC Vitamin trial - randomised controlled trial Can folic acid reduce neural tube defects (e.g. spina bifida)?

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

6. 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)?

7. Neural Tube Defects Yes No Total Folic Acid Yes 6 587 593 No 21 581 602 Folic Acid vs Placebo forNeural Tube Defects Lancet 1991 Risk of NTD in treated group = 1% Risk of NTD in control group = 3.5% Relative Risk of NTD in treated group compared to control group = 1%/3.5% = 0.29

8. Folic Acid vs Placebo forNeural Tube Defects RR = 0.29 P = 0.008 95% Confidence Interval : 0.10 to 0.76

9. 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 Can folic acid reduce neural tube defects (e.g. spina bifida)?

11. Planning the study – how large Analysing the results Stopping the study early (Independent Data Monitoring Committee) Statisticians Involvement

12. Women in MRC trial had had a previous NTD pregnancy and were given 4mg folic acid per day Current recommendation is 0.4mg folic acid per day What Dose ?

13. Dose Folic Acid Serum Folate Level ? Risk of NTD pregnancy

16. Dose Folic Acid Serum Folate Level Risk of NTD pregnancy

17. Folic Acid and NTD Dose Response

18. Folic Acid and NTD Dose Response

19. 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

20. Conclusions Women planning a pregnancy should take 5mg folic acid tablets daily, instead of the 0.4mg dose presently recommended (THE LANCET • Vol 358 • December 15, 2001)

21. MRC Trial

23. Fortification (0.2mg/day)

24. 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

25. 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

26. Unaffected Affected Biomarker : ZZ

27. Unaffected Affected Biomarker : ZZ Screen positive Screen negative

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

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

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

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

32. Detection Rate False Positive Rate

34. 4.2mm Hg

36. 7.5mm Hg

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

39. 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

40. 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

41. Method : Monte Carlo Simulation • Generate a population of 500,000 people aged 0-89 years. [Use Office for National Statistics Population Data for England and Wales] • Assign risk factors (eg diabetes, smoking, blood pressure) [Use Health of the Nation Survey] • Calculate a persons risk [Use Framingham risk equations] • Assign deaths according to people’s risks

43. Age is as good at predicting heart disease as measuring conventional risk factors Therefore treatment should be offered on the basis of age Conclusion

44. Blood Pressure Lowering Drugs What dose Which drug Treatment to Prevent Heart Disease

46. Each study may be relatively inconclusive because of too much uncertainty (too small) Meta-analysis : statistical method of combining and presenting results from several studies Can indicate more robust results Several studies looking at the same thing

47. Blood pressure reduction (mmHg)

48. Reduction in blood pressure People reporting side effects 20 mm Hg 10% 4% 7 mm Hg 1 Drug Standard dose 3 Drugs Half standard dose 1 Drug Standard dose 3 Drugs Half standard dose Major influence for prescription of combination therapy as first line of action

49. BMJ 2009;338:b1665