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

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

3. Folic Acid and Neural Tube Defects

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

5. Randomised Controlled Trial 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)

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

7. Folic Acid vs Placebo for Neural Tube Defects Lancet 1991 Neural Tube Defects YesNoTotal Folic Acid Yes6587593 No21581602 Risk of NTD in treated group = Risk of NTD in control group = Relative Risk of NTD in treated group compared to control group = 1% 3.5% 1%/3.5% = 0.29

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

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

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

12. What Dose ? 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

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

19. Interpretation 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

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. AffectedUnaffected Biomarker : ZZ

27. AffectedUnaffected Screen negative Screen positive Biomarker : ZZ

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

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

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

31. Is Cholesterol any good for screening ? AffectedUnaffected Risk screen converter screen http://www.wolfson.q mul.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 Total hCG Inhibin-A AFP uE 3 Down’s syndrome Unaffected Down’s syndrome Unaffected Down’s syndrome Unaffected

40. 1:10 8 1:10 6 1:10 4 1:10 2 1:1 10 2 :1 10 4 :1 Down’s syndrome Unaffected 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) 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. Conclusion Age is as good at predicting heart disease as measuring conventional risk factors Therefore treatment should be offered on the basis of age

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

46. Several studies looking at the same thing 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

47. Blood pressure reduction (mmHg)

48. Major influence for prescription of combination therapy as first line of action 1 Drug Standard dose 3 Drugs Half standard dose 1 Drug Standard dose 3 Drugs Half standard dose 7 mm Hg 20 mm Hg10% 4% Reduction in blood pressure People reporting side effects

49. BMJ 2009;338:b1665

53. A reduction in blood pressure of 20mm Hg halves the risk of a CHD event or stroke regardless of the person’s original blood pressure or their level of cardiovascular risk. This means that everyone at sufficient cardiovascular risk will benefit from a reduction in blood pressure, even if they don’t have a high blood pressure. For example all people with diabetes should be offered treatment. BMJ 2009;338:b1665

57. Involvement of Statistician Study design for clinical trial Analysing data from clinical trial Meta analysis from several trials Monte Carlo simulation using results above

58. Conclusion As much about collection, interpretation and presentation as calculation Making sense out of uncertainty