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

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

(e.g. spina bifida)
• MRC Vitamin trial - 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
• Randomised = allocated to groups on basis of chance e.g. tossing a coin (ensures fair comparison)
• Controlled = a comparison group

(e.g. spina bifida)
• MRC Vitamin trial - randomised controlled trial
• Large: 1817 women who had had a previous NTD, 33 centres, 7 countries

Folic
Acid
Yes
No
Folic Acid vs Placebo for
Neural Tube Defects
Lancet 1991
Neural Tube Defects
Yes
6
21
No
587
581
Total
593
602
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

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

(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

• Planning the study
• Analysing the results
• Stopping the study early (Data Monitoring
Committee)

• 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

Dose Folic Acid
Serum Folate Level
Risk of NTD pregnancy

Dose Folic Acid
Serum Folate Level
Risk of NTD pregnancy

Folic Acid and NTD Dose Response
0 2 4 6
Plasma folate (ng/ml)
8 10

0
Folic Acid and NTD Dose Response
2 4
Plasma folate (ng/ml)
6 8 10

• 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

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)

MRC Trial

Fortification
(0.2mg/day)

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

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

Unaffected
Biomarker : ZZ
Affected

Unaffected Affected
Biomarker : ZZ
Screen negative Screen positive

False negatives
False positives
FPR=5%
Unaffected Affected
Biomarker : ZZ
Screen negative Screen positive

Good test
Unaffected
Affected
Risk Factor

Poor test
Unaffected
Affected
Risk Factor

8
6
4
2
Risk screen converter http://www.wolfson.q
mul.ac.uk/rsc/
.2
fol
.4
.6
.8
Unaffected Affected

Detection Rate
False Positive Rate

4.2mm Hg

7.5mm Hg

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

Down’s syndrome
AFP
Quadruple test markers uE
3
Unaffected
Unaffected Down’s syndrome
0.25
0.5
1 2
Maternal serum AFP (MoM)
4 8 16 0.25
0.5
1 2
Maternal serum uE3 (MoM)
4 8 16
Unaffected
Total hCG
Down’s syndrome
Unaffected
Inhibin-A
Down’s syndrome
0.25
0.5
1 2 4
Maternal serum total hCG (MoM)
8 16 0.25
0.5
1 2 4
Maternal serum inhibin-A (MoM)
8 16

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
1:10 8 1:10 6 1:10 4 1:10 2 1:1 10 2 :1 10 4 :1
Risk of a Down’s syndrome pregnancy at term

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

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

• Blood Pressure Lowering Drugs
– What dose
– Which drug

• 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

Blood pressure reduction
(mmHg)

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

BMJ 2009;338:b1665

BMJ 2009;338:b1665
• 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.

• Study design for clinical trial
• Analysing data from clinical trial
• Meta analysis from several trials
• Monte Carlo simulation using results above
• Current work…

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