medical statistics joan morris ([email protected]) professor of medical statistics goldsmiths...
TRANSCRIPT
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Medical Statistics
Joan Morris ([email protected])Professor of Medical Statistics
Goldsmiths Lecture 2014
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Aims
• To give a brief description of some different areas of medical statistics
– Folic acid and Neural Tube Defects
– Screening for Heart Disease
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Folic Acid and Neural Tube Defects
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Can folic acid reduce neural tube defects (e.g. spina bifida)?
• MRC Vitamin trial - randomised controlled trial
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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)
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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
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Folic Acid vs Placebo forNeural Tube Defects
Lancet 1991
Neural Tube Defects
Yes No Total
Folic Acid
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
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Folic Acid vs Placebo forNeural Tube Defects
RR = 0.29
95% Confidence Interval : 0.10 to 0.76
P = 0.008
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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
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Statisticians Involvement
• Planning the study – how large
• Analysing the results
• Stopping the study early (Independent Data Monitoring Committee)
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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
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Dose Folic Acid
Serum Folate Level
Risk of NTD pregnancy
?
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Dose Folic Acid
Serum Folate Level
Risk of NTD pregnancy
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01
23
45
67
8N
TD
pre
vale
nce
per
10
00 b
irths
0 2 4 6 8 10Plasma folate (ng/ml)
Folic Acid and NTD Dose Response
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Folic Acid and NTD Dose Response01
23
45
67
8N
TD
pre
vale
nce
per
10
00 b
irths
0 2 4 6 8 10Plasma folate (ng/ml)
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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
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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)
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MRC Trial
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Fortification (0.2mg/day)
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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
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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
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AffectedUnaffected
Biomarker : ZZ
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AffectedUnaffected
Screen negative Screen positive
Biomarker : ZZ
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Screen negative Screen positive
Biomarker : ZZ
False positives
False negatives
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Risk Factor
Unaffected Affected
Good test
Screening for a medical disorder
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Risk Factor
Unaffected Affected
Poor test
Screening for a medical disorder
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Is Cholesterol any good for screening ?
2
4
6
8
.2 .4 .6 .8fol
AffectedUnaffected
Risk screen
converterhttp://
www.wolfson.qmul.ac.uk/rsc/
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Detection Rate
False Positive Rate
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4.2mm Hg
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7.5mm Hg
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• Are there any good screening tests ?
Antenatal screening for Down’s syndrome
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Quadruple test markers
0.25 0.5 1 2 4 8 16
Maternal serum total hCG (MoM)
0.25 0.5 1 2 4 8 16
Maternal serum inhibin-A (MoM)
Total hCG Inhibin-A
0.25 0.5 1 2 4 8 16
Maternal serum AFP (MoM)
0.25 0.5 1 2 4 8 16
Maternal serum uE3 (MoM)
AFP uE3
Down’s syndrome
Unaffected Down’s syndrome
Unaffected
Down’s syndrome
Down’s syndrome
Unaffected Unaffected
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01:108 1:106 1:104 1:102 1:1 102:1 104:1
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
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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
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Conclusion
• Age is as good at predicting heart disease as measuring conventional risk factors
• Therefore treatment should be offered on the basis of age
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Treatment to Prevent Heart Disease
• Blood Pressure Lowering Drugs– What dose– Which drug
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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
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Blood pressure reduction (mmHg)
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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 Hg 10%
4%
Reduction in blood pressure People reporting side effects
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BMJ 2009;338:b1665
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• 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
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Involvement of Statistician
• Study design for clinical trial
• Analysing data from clinical trial
• Meta analysis from several trials
• Monte Carlo simulation using results above
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Conclusion
As much about collection, interpretation and presentation as calculation
Making sense out of uncertainty