biostatistics case studies
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Biostatistics Case Studies
Peter D. Christenson
Biostatistician
http://gcrc.humc.edu/Biostat
Session 2: Diagnostic Classification
Case Study
PSA Background
• PSA secreted by prostatic epithelial cells; test developed in the late 1970s.
• Currently, usually screen PSA>4.0 ng/ml.• Why 4.0? Unclear; early studies of CaP patients
showed many PSA > 4.0?• Hesitant to unnecessarily take biopsies with lower
PSA.• A few studies did suggest substantial CaP with
lower PSA.• Prostate Cancer Prevention Trial specified biopsy
at study end, regardless of PSA.
Issues and Goals
Over-diagnosis in men over 50:• Microscopic evidence in 33% of autopsy /
cystoprostatectomy specimens.• 9-16% currently diagnosed with CaP.• 3% CaP mortality.
Screening (early diagnosis):Maximize curable CaP detection and exclude as
many men as possible from unnecessary biopsies.
Prognosis (predicting outcome):Predict mortality using pre- and post-biopsy info.
Catalona, et al (1991)
• Men ≥ 50 years of age with PSA ≥ 4.0.• Biopsy those with abnormal DRE or
ultrasound.
N=1653
N=1516 N=107 (6.5%) N=30 (1.8%)
N=85 N=27
N=19/85=22% N=18/27=67%
PSA<4.0 PSA≥104.0≤PSA<10
?
Abnormal DRE / US
CaP in biopsy
Krumholtz, at al (2002)
• Prostate screening program. Recommend biopsy if high PSA and/or abnormal DRE. PSA cutoff changed from 4.0 to 2.6 mid-study.
• CaP in 156/601=26% with 2.6≤PSA≤4.0 and 97/309=31% with 4.0<PSA≤10.0.
• Report on 94 with embedded prostatectomy specimens.• PSA≤4.0 more organ-confined; not greater over-
detection.
Prostate Cancer Prevention Trial (PCPT)
18,882 men randomized to finasteride or placebo; up to 7 years follow-up.
Annual DRE and PSA. Biopsy recommended if PSA>4.0 or abnormal DRE. End of study biopsy planned for all men without during-study diagnosis of CaP.
Primary outcome = biopsy CaP positive or negative.
Main result: finasteride had 25% efficacy; 18% CaP in finasteride vs. 24.4% CaP in placebo.
Current Paper: Thompson et al, 2004.
Main Results
Overall, 449/2950 = 15.2% with CaP detected in biopsy.
Conclusions and Issues
There is substantial CaP with low PSA values, and the rate appears to have a dose-response relationship with PSA.
Is it a good screening tool?
Does it have prognostic ability, at least for CaP in biopsy, since mortality was not studied.
What do we make of the reported sensitivity and specificity?
We first examine several “what if” scenarios with artificial data.
Scenario 1: PSA is useless
420
PSA
Ca
P
No
Yes
24.4% 24.4%
Scenario 2: PSA is a perfect test
420
Yes
No
PSA
Ca
P
0 / 2950 = 0%
1187 / 1187 = 100%
Scenario 3: Almost perfect association
% C
aP
PSA4.02.0
90
70
50
30
10
PSA Prognostic Ability in Scenario 3
Predict P(CaP) = Probability(CaP) using PSA:
P(CaP if PSA = 3) = 33 ± 2 % (CI)
P(CaP if PSA = 8) = 88 ± 2 % (CI)
Since ±2% is very small, this study is very precise at measuring the prevalence of biopsy-evident CaP according to PSA intervals.
PSA would be a decent prognostic factor for biopsy-detected CaP (but of course we actually want to predict clinical outcomes).
PSA Screening Ability
Sensitivity = True positive rate
= % identified among CaP +.
Specificity = True negative rate
= % not identified among CaP -.
For screening, sensitivity is usually more important than specificity.
PSA Screening Ability in Scenario 3using PSA>4.0
Sensitivity = 820/(820+449) = 65%
Specificity = 2501/(2501+367) = 87%
% C
aP
PSA4.02.0
90
70
50
30
10
+ CaP: N= 449- CaP: N=2501
+ CaP: N=820- CaP: N=367
PSA Screening Ability in Scenario 3using PSA>2.0
Sensitivity = 987/(987+282) = 78%
Specificity = 1993/(1993+875) = 55%
% C
aP
PSA4.02.0
90
70
50
30
10
+ CaP: N= 282- CaP: N=1993
+ CaP: N=987- CaP: N=875
Conclusions from ScenariosAssociation ≠ screening accuracy.
Good* screening needs something more like:
*Few unnecessary biopsies, but detect most serious CaP.
% C
aP
PSA4.02.0
75
55
35
15
Back to Actual Results:
Overall, 449/2950 = 15.2% with CaP detected in biopsy.
Revised Table 2:Prevalence of CaP and its Precision
95% CI for CaP Prevalence
PSA Range Any Grade High Grade
≤ 0.50 6.6 ± 2.2% 0.8 + 0.8%
0.6 – 1.0 10.1 ± 2.1% 1.0 ± 0.7%
1.1 – 2.0 17.0 ± 2.4% 2.0 ± 0.9%
2.1 – 3.0 23.9 ± 3.9% 4.6 ± 1.9%
3.1 – 4.0 26.9 ± 6.4% 6.7 ± 3.6%
≤ 4.0 15.2 ± 1.3% 2.3 ± 0.5%
Table 2: Sensitivity and Specificity
Sensitivity at PSA=1.1 of 0.75 = (170+115+52)/449
Specificity at PSA=1.1of 0.33=(486-32 +791-80)/(2950-449)
Relative to only PSA≤4.0. Not useful without PSA>4.0 info.
Figure 2: Models P(CaP)=function(PSA)
Risk=
P(CaP)
Figure 2 Models Table 2 Data
Dotted line is only to show form of model; do not extrapolate.
Logistic model is not very useful with so much data, unless adjustment for other factors (e.g., family hx of CaP) is desired.
109876543210
80
60
40
20
0
PSA
P(
Ca
P )
Figure 2 Logistic Model
Table 2 CIs? after PSA>4
Logistic Regression• Uses odds of disease = P(CaP)/[1-P(CaP)].
• Log(odds) are linear in PSA sigmoidal curve in previous graph, common for bounded outcomes.
• Increase in odds for a given change in PSA is proportional to PSA.
• For this study, log(odds)= -2.70 + 0.507(PSA) and
P(CaP) = exp(logodds)/(1+exp(logodds)
• Can include other adjusting factors.
• Usually used for prediction (prognosis); but can define, e.g., Prob(CaP)=fixed number such as 0.22 to classify and obtain sensitivity and specificity.
Logistic Regression in Software
SPSS:
Select Analyze > Regression > Binary Logistic
Specify CaP (1=Yes;0=N0) as dependent variable.
Specify PSA as covariate.
Select Options > CI for exp(B). OK
SAS:
proc logistic descending;
class CaP;
model CaP = PSA;
run;
Software Output: SAS
Odds Ratio Estimates
Point 95% WaldEffect Estimate Confidence Limits
PSA 1.66 1.50 1.85
Analysis of Maximum Likelihood Estimates
Parameter DF Estimate
Intercept 1 -2.700 PSA 1 0.507
Combined Screening and Prognosis ?
PSAOtherPre-
Biopsy1
BiopsyCharacter-
istics2
Risk ofCaP
Death
Biopsy
Biopsy
Moderate
Low
High
Neg
Neg
Pos
Pos
1 Such as PSA velocity2 Such as prostate volume See NEJM 2004(Jul 8);351:125-135.
Summary
• This paper does not address PSA screening ability.
• Demonstrates substantial CaP even with very low PSA.
•Study in progress with mortality as outcome (Ref 29).
• Studies in progress using additional markers for early detection and of CaP (Ref 30).
• Possible prediction error in any study due to lab error in measuring PSA. Here, if large, say 20%,
20% error =~ 10% error in Prob(CaP).
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