actalecturerungsted
TRANSCRIPT
Science = generalizable knowledge
Predictive and reliable information
Collected in some subjects and generalized to others
Sampling problems often exists, but not always
Qualitative research methods
Are only meaningful without sampling problems(constant outcome, deterministic events)
or when sampling problems are irrelevant(one observation is sufficient to reject the hypothesis)
Quantitative methods (statistical)
Are used to quantify sampling uncertainty
Sampling uncertainty is caused by variability
Statistics is primarily about variability
The confusing EQ-5D index
A study of variability
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Swedish Knee Arthoplasty Register
The distribution is important when discussing improvement
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The Poisson distribution
Siméon Poisson (1781–1840)
Defined by: λ
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The Gaussian distribution
Abraham de Moivre (1667–1754)
Defined by: µ and σ (the latter usually assumed constant)
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Xie F Li S-C, Luo N, LO N-N,Yeo S-J,Yang KY, Fong KY, Thumboo J. Comparison of the EuroQol and Short Form 6D in Singapore Multiethnic Asian Knee Osteoarthritis Patients Scheduled for Total Knee Replacement. Arthritis & Rheumatism (Arthritis Care & Research) 2007;57:1043–1049
Empirical EQ-5D distribution
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A Gaussian mixture distribution?
Defined by: µ1,µ
2,σ
1,σ
2 and w
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Mean = 0.58SD = 0.21
Mean = 0.58SD = 0.21
70%13%
87%
30%
!
Hospital A Hospital B
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Studying change in EQ-5D
It has been suggested that pairwise differences between pre- and postoperative EQ-5D values are normally distributed and can be meaningfully interpreted.
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Studying change in EQ-5D
It has been suggested that pairwise differences between pre- and postoperative EQ-5D values are normally distributed and can be meaningfully interpreted.
It can easily be shown that this is not correct
The sum of two bimodal distribution has a distribution with three modes, the difference four.
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Preop EQ-5D Postop EQ-5D
Delta EQ-5D
Empirical EQ-5D data from knee patients in Trelleborg 2007-2008
Delta EQ-5D
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Additional problem with analyses of change
Change is confounded by association with baseline
X = pre-operative (baseline) value Y = postoperative (follow up) value
Y-X correlates with X
Solution
When analyzing change, adjust for imbalance at baseline
(This is an almost perfect case-mix adjustment!)
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2. Gävleborg2. Kronoberg
1. Stockholm
3. Östergötland
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1. Stockholm
2. Kronoberg
2. Gävleborg
3. Östergötland
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EQ-5D ProblemsConventional analyses
Mean values not interpretable
Confidence intervals not reliable (Calculated assuming Gaussian distribution)
P-values not reliable (Student's t-test, ANOVA, etc. requires Gaussian distribution and homogeneous variance)
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EQ-5D Problems cont'd
Non-parametric analysis
Median value may not exist.
Confidence intervals not reliable (calculated assuming Gaussian or binomial distribution).
P-values not reliable (Wilcoxon's MPSR-test requires a symmetrical distribution, Mann-Whitney U-test requires distributions with identical shape.
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EQ-5D Problems cont'd
Adjusting for baseline
How meaningful is the outcome of an ANCOVA with variables having non-Gaussian, multimodal distributions (with different number of modes)? What do these residuals look like?
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EQ-5D Problems cont'd
Alternative analyses methods?
- Mixture distribution analysis (mixdist library for R)
- Multi-state Markov analysis (msm library for R)
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“This is about clinical improvement, not science”
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Swedish law defines clinical improvement work (CIW) as “not research”
Some CIW projects include experiments on patients
- No ethics approval is required (or can be applied for)- No informed consent- No scientific planning or evaluation of the experiments- No formal publication of studies and results
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Regression analysis
- Adjusting for baseline
- Models only including statistically significant factors
- Stepwise regression methods
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What factors should be included in a linear model (ANCOVA)?
Y = b0 + b
1X
1 + b
2X
2 + … + b
nX
n + e
This is a multiple or multivariable analysis but not multivariate.
Xi is a variable (factor or covariate)
bi is the effect on Y of one unit change in X
i
Assume that Y is blood pressure and X1 an indicator of anti-
hypertensive treatment. bi will then estimate the treatment effect in
terms of blood pressure reduction.
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Linear models
Answer
It depends on a) the purpose of the study and b) the study design used.
1. Purpose: (black-box) prediction
Any variable can be included as long as it increases the sensitivity and specificity of the prediction, and as long as results (b
i) are not
interpreted in terms of causal effects.
2. Purpose: effect estimation
The variables needed to produce valid (bi and their s.e.) should be
included.
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Linear models
1. Common for all designs
Include baseline when analyzing change in a continuous variable.
2. Randomized trial
Include randomization stratification factors (for valid standard errors).
3. Observational study
Include potential confounding factors (for valid regression coefficients).
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Linear models
How should confounding factors be included?
1. By the investigator's reasoning.
2. By reviewing other publications on the same endpoint.
3. By performing sensitivity analyses.
4. But not by using hypothesis testing or stepwise regression analysis.
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Parsons et al. A systematic survey of the quality of research reporting in general orthopaedic journals. J Bone Joint Surg Br 2011;93-B,1154-9
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