Medical Statistics
Joan Morris (j.k.morris@qmul.ac.uk)
Professor of Medical Statistics
Goldsmiths Lecture 2014
Aims
• To give a brief description of some
different areas of medical statistics
– Folic acid and Neural Tube Defects
– Screening for Heart Disease
Folic Acid and
Neural Tube Defects
Can folic acid reduce neural tube
defects (e.g. spina bifida)?
• MRC Vitamin trial - randomised controlled
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
• Controlled = a comparison group
• Randomised = allocated to groups on basis of
chance e.g. tossing a coin (ensures fair
comparison)
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
Folic Acid vs Placebo for
Neural Tube Defects
Lancet 1991
Neural Tube Defects
Folic
Acid
Yes
No
Total
Yes
6
587
593
No
21
581
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
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
Statisticians Involvement
• Planning the study – how large
• Analysing the results
• Stopping the study early (Independent
Data Monitoring Committee)
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
Dose Folic Acid
?
Serum Folate
Level
Risk of NTD
pregnancy
Dose Folic Acid
Serum Folate Level
Risk of NTD
pregnancy
0
1
2
3
4
5
6
7
8
Folic Acid and NTD Dose Response
0
2
4
6
Plasma folate (ng/ml)
8
10
0
1
2
3
4
5
6 7 8
Folic Acid and NTD Dose Response
2
4
Plasma folate (ng/ml)
6
8
10
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
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)
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
Affected
Biomarker : ZZ
Unaffected
Affected
Biomarker : ZZ
Screen negative
Screen positive
False
negatives
False
positives
Biomarker : ZZ
Screen negative
Screen positive
Screening for a medical disorder
Good test
Affected
Unaffected
Risk Factor
Screening for a medical disorder
Poor test
Affected
Unaffected
Risk Factor
Is Cholesterol any good for
screening ?
8
6
Risk
screen
converter
4
2
http://www.wolfson.q
mul.ac.uk/rsc/
.2
.4
.6
.8
fol
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
Quadruple test markers
AFP
Down’s
syndrome
0.25
uE3
Unaffected
0.5
1
2
Unaffected
Down’s
syndrome
4
8
16
0.25
0.5
Maternal serum AFP (MoM)
1
0.25
0.5
2
8
16
8
16
Inhibin-A
Unaffected
Down’s
syndrome
1
4
Maternal serum uE3 (MoM)
Total hCG
Unaffected
2
4
Maternal serum total hCG (MoM)
8
16
0.25
0.5
Down’s
syndrome
1
2
4
Maternal serum inhibin-A (MoM)
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
1:10
102:1
Risk of a Down’s syndrome pregnancy at term
104:1
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
Conclusion
• Age is as good at predicting heart disease
as measuring conventional risk factors
• Therefore treatment should be offered on
the basis of age
Treatment to Prevent Heart
Disease
• Blood Pressure Lowering Drugs
– What dose
– Which drug
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
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.
Involvement of Statistician
•
•
•
•
Study design for clinical trial
Analysing data from clinical trial
Meta analysis from several trials
Monte Carlo simulation using results
above
Conclusion
As much about collection, interpretation and
presentation as calculation
Making sense out of uncertainty