1. Welcome Back From Lunch

2. Thursday Afternoon
1:30-2:15 Studies and Systematic Review of Diagnostic Test Accuracy (Tom)
2:15-3:00 Prognostic and Genetic Tests (Mark)
3:00-3:45 Combining Tests (Michael)
3:45-4:00 Break
4:00-6:00 Small Groups
6:00 Meet in 6702 to head to Giants game

3. Studies of Diagnostic Test Accuracy
After lunch. Tom again or Michael to start with incorporation and spectrum bias?

4. Checklist
Was there an independent, blind comparison with a reference (“gold”) standard of diagnosis?
Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom we would use it in practice)?
Was the reference standard applied regardless of the diagnostic test result?
Was the test (or cluster of tests) validated in a second, independent group of patients?
From Sackett et al., Evidence-based Medicine,2nd ed. (NY: Churchill Livingstone), p 68

5. Beyond the Checklist
Consider not only possibility of bias, but WHY it may occur and DIRECTION it would affect results
Incorporation bias
Spectrum bias
Verification bias
Double gold standard bias

6. Incorporation Bias
When the test itself can be incorporated into the gold standard
Prevented by blinding

7. Example: Study of BNP as a test for congestive heart failure (CHF)*
Gold standard: determination of CHF by two cardiologists blinded to BNP
“The best clinical predictor of congestive heart failure was an increased heart size on chest roentgenogram (accuracy, 81 percent)”
Is there a problem with assessing accuracy of chest x-rays to diagnose CHF in this study?
*Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347(3): Problem 4.3

8. Incorporation bias Cardiologists not blinded to Chest X-ray
Used (incorporated) Chest x-ray for CHF diagnosis
Incorporation bias for assessment of Chest X-ray, not BNP

9. Spectrum of Disease and Nondisease
Disease is often easier to diagnose if severe
“Nondisease” is easier to diagnose if patient is well than if the patient has other diseases

10. Spectrum Bias
Sensitivity depends on the spectrum of disease in the population being tested.
Specificity depends on the spectrum of non-disease in the population being tested.
Example: Absence of Nasal Bone (on 13-week ultrasound) as a Test for Chromosomal Abnormality

11. Spectrum Bias Example: Absence of Nasal Bone as a Test for Trisomy 21*
Sensitivity = 229/333 = 69%
Specificity = 5094/5223 = 97.5%
BUT the D- group only included chromosomally normal fetuses
Cicero et al., Ultrasound Obstet Gynecol 2004; 23:

12. Spectrum Bias: Absence of Nasal Bone as a Test for Chromosomal Abnormality
D- group excluded 295 fetuses with other chromosomal abnormalities (esp. Trisomy 18)
Among these fetuses, 32% had absent nasal bone (not 2.5%)
What decision is this test supposed to help with?
If it is whether to test chromosomes using chorionic villus sampling or amniocentesis, these 295 fetuses should be included in D+ group!

13. Spectrum Bias: Absence of Nasal Bone as a Test for Chromosomal Abnormality, effect of including other trisomies in D+ group
Sensitivity = 324/628 = 52%
NOT 69% obtained when the D+ group only included fetuses with Trisomy 21

14. Verification bias: Example
Visual assessment of jaundice in newborns
Study patients who are getting a bilirubin measurement
Ask clinicians to estimate extent of jaundice at time of blood draw

15. Visual Assessment of jaundice*: Results
Sensitivity of jaundice below the nipple line for bilirubin ≥ 12 mg/dL = 97%
Specificity = 19%
What is the problem?
Editor’s Note: The take-home message for me is that no jaundice below the nipple line equals no bilirubin test, unless there’s some other indication.
--Catherine D. DeAngelis, MD
*Moyer et al., Archives Pediatr Adol Med 2000; 154:391

16. Verification Bias*
Inclusion criterion for study: gold standard test was done
in this case, blood test for bilirubin
Subjects with positive index tests are more likely to be get the gold standard and to be included in the study
clinicians usually don’t order blood test for bilirubin if there is little or no jaundice
How does this affect sensitivity and specificity?
*AKA Work-up, Referral Bias, or Ascertainment Bias

17. Verification Bias Effects
TSB >12
TSB < 12
Jaundice below nipple a b
No jaundice below nipple
c 
d 
Don’t change slide yet
Sensitivity, a/(a+c), is biased ___.
Specificity, d/(b+d), is biased ___.
*AKA Work-up, Referral Bias, or Ascertainment Bias

18. Double Gold Standard Bias-1
Two different “gold standards”
One gold standard (e.g., surgery, invasive test) is more likely to be applied in patients with positive index test
Other gold standard (e.g., clinical follow-up) is more likely to be applied in patients with a negative index test.

19. Double Gold Standard Bias- 2
There are some patients in whom the two “gold standards” do not give the same answer
Spontaneously resolving disease (positive with immediate invasive test, but not with follow-up)
Newly occurring or newly detectable disease (positive with follow-up but not with immediate invasive test)

20. Double Gold Standard Bias, example
Study Population: All patients presenting to the ED who received a V/Q scan
Test: V/Q Scan
Disease: Pulmonary embolism (PE)
Gold Standards:
1. Pulmonary arteriogram (PA-gram) if done (more likely with more abnormal V/Q scan)
2. Clinical follow-up in other patients (more likely with normal VQ scan
What happens if some PE resolve spontaneously?
*PIOPED. JAMA 1990;263(20):

21. Effect of Double Gold Standard Bias 1: Spontaneously resolving disease
Test result will always agree with gold standard
Both sensitivity and specificity increase
Example: Joe has a small pulmonary embolus (PE) that will resolve spontaneously.
If his VQ scan is positive, he will get an angiogram that shows the PE (true positive)
If his VQ scan is negative, his PE will resolve and we will think he never had one (true negative)
VQ scan can’t be wrong!

22. Effect of Double Gold Standard Bias 2: Newly occurring or newly detectable disease
Test result will always disagree with gold standard
Both sensitivity and specificity decrease
Example: Jane has or will soon get a nasty breast cancer that is currently undetectable
If her mammogram is positive, she will get biopsies that will not find the tumor (mammogram will look falsely positive)
If her mammogram is negative, she will return in several months and we will think the tumor was initially missed (mammogram will look falsely negative)
Mammogram can’t be right!

23. Effect of Double Gold Standard Bias
Newly occurring or newly detectable disease
Sensitivity falsely decreased
Specificity falsely decreased
Spontaneously resolving disease
Sensitivity falsely increased
Specificity falsely increased

24. Sensitivity is falsely … Specificity is falsely …
Bias
Description
Sensitivity is falsely …
Specificity is falsely …
Incorporation
Gold standard incorporates index test.
Spectrum
D+ only includes “sickest of the sick”
D- only includes “wellest of the well:
Verification
Positive index test makes gold standard more likely.
Double Gold Standard
Disease resolves spontaneously
Disease become sdetectable during follow-up

25. Systematic Reviews of Diagnostic Accuracy Studies

26. Meta-analyses of Diagnostic Tests
Systematic and reproducible approach to finding studies
Summary of results of each study
Investigation into heterogeneity
Summary estimate of results, if appropriate
Unlike other meta-analyses (risk factors, treatments), results aren’t summarized with a single number (e.g., RR), but with two related numbers (sensitivity and specificity)
These can be plotted on an ROC plane

27. MRI for the diagnosis of MS
Whiting et al. BMJ 2006;332:875-84

28. Dermoscopy vs Naked Eye for Diagnosis of Malignant Melanoma
Dermoscopy performed unequivocally better in 7 of the 9 studies. Can you circle results for the 2 studies for which this was not the case?
Br J Dermatol Sep;159(3):669-76

29. Kharbanda et al. Pediatrics 2005; 116(3): 709-16
Example: A clinical decision rule to identify children at low risk for appendicitis (Problem 5.6)
Study design: prospective cohort study
Subjects
4140 patients 3-18 years presenting to Boston Children’s Hospital ED with abdominal pain
Of these, 767 (19%) received surgical consultation for possible appendicitis
113 excluded (chronic diseases, recent imaging)
53 missed
601 included in the study (425 in derivation set) 9
Kharbanda et al. Pediatrics 2005; 116(3):

30. Kharbanda et al. Pediatrics 2005; 116(3): 709-16
A clinical decision rule to identify children at low risk for appendicitis
Predictor variable
Standardized assessment by pediatric ED attending
Focus on “Pain with percussion, hopping or cough” (complete data in N=381)
Outcome variable:
Pathologic diagnosis of appendicitis (or not) for those who received surgery (37%)
Follow-up telephone call to family or pediatrician 2-4 weeks after the ED visit for those who did not receive surgery (63%)
Kharbanda et al. Pediatrics 2005; 116(3):

31. Kharbanda et al. Pediatrics 2005; 116(3): 709-16
A clinical decision rule to identify children at low risk for appendicitis
Results: Pain with percussion, hopping or cough
78% sensitivity and 83% NPV seem low to me. Are they valid for me in deciding whom to image?
Kharbanda et al. Pediatrics 2005; 116(3):

32. Checklist
Was there an independent, blind comparison with a reference (“gold”) standard of diagnosis?
Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom we would use it in practice)?
Was the reference standard applied regardless of the diagnostic test result?
Was the test (or cluster of tests) validated in a second, independent group of patients?
From Sackett et al., Evidence-based Medicine,2nd ed. (NY: Churchill Livingstone), p 68

33. In what direction would these biases affect results?
Sample not representative (population referred to pedi surgery)?
Verification bias?
Double-gold standard bias?
Spectrum bias
Sample NOT representative. Prevalence of Appy too high for decision about imaging
Verification bias probably operating – lack of pain with hopping would make me LESS likely to seek surgical consultation. But this would bias sensitivity UP.
DGSB COULD be a bias, if some cases of appendicitis spontaneously resolve, but this would bias sensitivity and specificity UP
Spectrum bias probably operates for Specificity, not Sensitivity. Presumably the non-appy cases referred to pedi surgery looked more like appendicitis, therefore likely to have higher FP rate for pain with hopping than those note studied

34. For children presenting with abdominal pain to SFGH 6-M
Sensitivity probably valid (not falsely low)
But whether all of them tried to hop is not clear
Specificity probably low
PPV is too high
NPV is too low
Does not address surgical consultation decision

35. Prognostic and Genetic Tests (Mark)