ebm-diagnostic testing k. mae hla, md, mhs primary care faculty development fellowship
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EBM-Diagnostic Testing K. Mae Hla, MD, MHS Primary Care Faculty Development Fellowship November 13, 2010. Objectives. Develop pre-test probabilities Derive treatment thresholds Appraise evidence about a diagnostic test -validity, accuracy and applicability - PowerPoint PPT PresentationTRANSCRIPT
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EBM-Diagnostic Testing
K. Mae Hla, MD, MHS
Primary Care Faculty
Development Fellowship
November 13, 2010
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Objectives
• Develop pre-test probabilities • Derive treatment thresholds• Appraise evidence about a diagnostic test
-validity, accuracy and applicability• Calculate the results of diagnostic tests
-sensitivity, specificity and likelihood ratios• Apply evidence to patient care decisions
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The Diagnostic Process
• Working diagnosis- pretest probability• With each new finding/test we move
from the pre-test probability to a new post-test probability
• Clinicians estimate probability of disease using probabilistic, prognostic and pragmatic approaches
• Compare disease probabilities to two thresholds
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Applying Diagnostic Tests
Example #1
8-year-old with fever, sore throat, swollen cervical glands and tonsillar exudates. No h/o cough.
You order a rapid strep test.
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What’s your pretest probability of the patient having group A strep pharyngitis?
How much of a change would help you decide to treat, not treat or test further?
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 100%
Probability of Strep Pharyngitis
5% 90%
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Rapid Strep Test Results
Rapid Strep test result comes back negative
How does the rapid strep test result change the probability of the patient having or not having the disease?
A positive rapid strep test raises post test probability of strep pharyngitis to 85% in one study
A negative strep test decreases probability to 12 %
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Pre-test Prob = 40%
LR+ =
LR- =
7.2
0.24
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 12% 100%
Probability of strep when rapid strep test
is negative
X
5% 90%
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Example #2
18-year-old female with ankle pain after a roller-blading accident. States unable to walk on her injured ankle. Exam demonstrates a slightly swollen ankle but no tenderness noted. Able to bear weight and take 4 full steps upon encouragement.
What is the probability of ankle fracture?
Do you need to order an ankle x-ray?
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Ottowa Ankle rule
An ankle x-ray is only necessary if there is pain near the malleoli and any of the following findings are present:
inability to bear wt. both immediately and in the ED
bone tenderness at the posterior edge or tip of the malleolus
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How accurate is the Ottowa ankle rule in ruling out ankle
fracture?
A prospective validation study in > 1000 pts presenting to the ED with ankle pain
Likelihood ratio + = 1.96
Likelihood ratio - = 0
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Pre-test Prob = 10%
LR+ =
LR- =
1.96
0
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Case 1• 75-year-old woman with a hemoglobin
of 10, MCV was 80 on routine checkup, a negative history and physical except osteoarthritis, and on no meds likely to suppress her marrow or cause a bleed
• Her probability of iron deficiency was 50%
• You want to avoid doing a bone marrow and order serum ferritin to diagnose iron deficiency anemia
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Case 1• P: In an elderly symptomless woman with
mild anemia• I: how useful is serum ferritin • C:• O: in diagnosing iron deficiency anemia• T(ype of question): Diagnosis• T(ype of study): Prospective Cohort
*Diagnosis of Iron Deficiency Anemia in the Elderly (Guyatt, et al. Am J Med, 1990;(88):205-209
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Three Main Questions
• Validity-Is this evidence about the accuracy of a diagnostic test valid?
• Results-Does this evidence show that this test can adequately distinguish patients who do and do not have the disorder?
• Applicability-How can I apply this valid, accurate diagnostic test to a specific patient?
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Validity
• Measurement: was the gold standard measured independently?
• Representative: was the test evaluated in appropriate spectrum of patients?
• Ascertainment: was the reference test ascertained regardless of the diagnostic test?
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• All patients in study should have both the diagnostic test in question (blood test, history, physical exam) and the gold/reference standard test (autopsy, bone marrow, biopsy, angiogram)
• Independent- test not part of gold standard, decision to perform gold standard should not depend on result of diagnostic test under study
• Blinding- reference test readers should be unaware of results to avoid bias if tests/gold standard have subjective component- x-rays, biopsy, slides
Validity- Measurement
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Validity: Measurement
• Was there an independent blind comparison with a reference gold standard? • The gold standard was the bone marrow
aspirate results• All patients got the serum ferritin and
bone marrow done independently • Marrow aspirates and iron deficiency
status was determined by 2 hematologists unaware of the lab result
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Validity: Representative
• Was the diagnostic test evaluated in an appropriate spectrum of patients?
• Examples: risk markers such as CEA were initially done in high risk patients
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Validity: Representative
• Diagnostic uncertainty• Patients with mild as well as severe
symptoms• Patients with early as well as late
disease• Patients with other commonly
confused diagnoses
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Study spectrum representative?
• Consecutive patients age 65 or older with anemia were recruited
• 36% of patients had iron deficiency anemia• 44% had anemia of chronic disease• 8% megaloblastic anemia• Patients with other commonly confused
disorders- different types of anemia and chronic medical conditions were included
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Validity: Ascertainment
• Was the reference standard ascertained regardless of the diagnostic test result?
• Did all patients in the study both with and without iron deficiency anemia get the bone marrow done?
• Yes
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• Patients with negative diagnostic test may not get the gold standard done if the latter is invasive
• How do we prove for sure that the ones with negative tests truly do not have the disease or vice versa?
• Other ways to establish reference test
Ascertainment-Continued
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• In the Pioped study looking at the utility of V/Q scan in patients with suspected pulmonary embolism-all patients with negative V/Q scan did not get pulmonary angiogram
• Clinical followup in a year was the
additional reference standard to not miss patients with false negative VQ results
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Results
• Does the test accurately distinguish between patients with and without the disorder?– Sensitivity and specificity– Likelihood ratios
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa bb a+ba+b
NegativeNegativecc dd c+dc+d
a+ca+c b+db+d
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa
TPTP
bb
FPFP
a+ba+b
NegativeNegativecc
FNFN
dd
TNTN
c+dc+d
a+ca+c b+db+d
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa
TPTP
bb
FPFP
a+ba+b
NegativeNegativecc
FNFN
dd
TNTN
c+dc+d
a+ca+c
Sen=a/a+cSen=a/a+c
b+db+d
Sp=d/d+bSp=d/d+b
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa
TPTP
bb
FPFP
a+ba+b
NegativeNegativecc
FNFN
dd
TNTN
c+dc+d
a+ca+c
Sen=a/a+cSen=a/a+c
Sp=d/d+bSp=d/d+b
b+db+d
““PID”PID”
““NIH”NIH”
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Sensitive test-rules out the disease (SnNout)
• Test with high sensitivity (high TPR and very low false negative rate), negative test rules out the disease
• Examples: • loss of retinal vein pulsation in increased
intracranial pressure-the presence of pulsation (negative test) rules out IIP
• HIV antibody- negative test rules out HIV
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Specific test – rules in the disease (SpPIN)
• Test with high specificity (high TNR, very low FPR)-positive test rules in the diagnosis
• Features of child with Down’s syndrome-very specific
• Presence of features (positive test) rules in the diagnosis
• Western blot confirmatory testing for HIV- high specificity: positive test rules in HIV disease
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Likelihood RatioLikelihood Ratio
likelihood of the test result in patients with the diseaselikelihood of the same result in patients without diseaseLR =LR =
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa
TPTP
bb
FPFP
a+ba+b
NegativeNegativecc
FNFN
dd
TNTN
c+dc+d
a+ca+cSen=a/a+cSen=a/a+c
b+db+dSp=d/d+bSp=d/d+b
(+)LR= (+)LR= + test result in pts with dz+ test result in pts with dz (-)LR= (-)LR= - test result in pts with dz- test result in pts with dz + test result in pts without dz - test result in pts without dz+ test result in pts without dz - test result in pts without dz
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DiseaseDisease
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositiveaa
TPTP
bb
FPFP
a+ba+b
NegativeNegativecc
FNFN
dd
TNTN
c+dc+d
a+ca+cSen=a/a+cSen=a/a+c
b+db+dSp=d/d+bSp=d/d+b
(+)LR= (+)LR= + test result in pts with dz+ test result in pts with dz (-)LR= (-)LR= - test result in pts with dz- test result in pts with dz + test result in pts without dz - test result in pts without dz+ test result in pts without dz - test result in pts without dz
= Sn/1-Sp = 1-Sn/Sp= Sn/1-Sp = 1-Sn/Sp
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Likelihood RatioLikelihood Ratio
probability of the test result in patients with the diseaseprobability of the same result in patients without diseaseLR =LR =
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Pre-Test Probability
Pre-Test Odds
Post-Test Odds
Post-Test Probability
Odds = Probability/1-probability Probability = Odds/1 + Odds
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What do all these numbers mean?!?
• L.R.s indicate by how much a given diagnostic test result will raise or lower the pre-test probability of the target disorder
• L.R. of 1 = post-test probability is same as pre-test probability
• L.R. > 1 increases the probability that the target disorder is present; the higher the L.R., the greater the increase
• L.R. < 1 decreases the probability of the target disorder; the smaller the L.R., the greater the decrease
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Effects of different likelihood ratios
• >10 or <0.1 generate large and often conclusive changes from pre- to post-test probability
• 5-10 and 0.1-0.2 generate moderate shifts in pre- to post-test probability
• Depending on pre-test probability, change may or may not be large enough to influence Rx decision
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Back to our patient
Our patient’s serum ferritin comes back at 40 mmol/L
How should we put all this together?
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Iron Deficiency AnemiaIron Deficiency Anemia
PresentPresent AbsentAbsent
TT
ee
ss
tt
PositivePositive
<<4545
7070
aa
1515
bb
NegativeNegative
>45>45
cc
1515
dd
135135
a+ca+c b+db+d a+b+c+da+b+c+d
TotalsTotals 8585 150150 235235
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Low ferritin (<45) in diagnosing Fe def anemia
Prevalence (study pre-test probability)
= 85/235= 36%
Sensitivity = True positive / all with disease
= a/a+c
= 70/85
= 82%
Specificity = True neg / all without disease
= d/b+d
= 135/150
= 90%
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Low ferritin (<45) in diagnosing iron deficiency
anemia
L.R.+ = sensitivity/(1-specificity)
= 82%/10% = 8.2
L.R. - = (1-sens)/spec
= 18%/90% = 0.2
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Simplifying Likelihood Simplifying Likelihood Ratio CalculationsRatio Calculations
Bone Marrow: Bone Marrow:
iron deficientiron deficient
Bone Marrow: Bone Marrow: normal ironnormal iron
Test Results:Test Results:
<< 45 45 7070 1515
>> 46 46 1515 135135
TotalsTotals 8585 150150
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Calculating Likelihood Ratios at 45 cut point
Bone Marrow: Bone Marrow:
iron deficientiron deficient
Bone Marrow: Bone Marrow: normal ironnormal iron
Likelihood Likelihood RatiosRatios
Test Results:Test Results:
<< 45 45 7070
70/85=0.82470/85=0.824
1515
15/150=0.115/150=0.1
0.824/0.1=0.824/0.1=
8.248.24
>> 46 46 1515
15/85=0.17615/85=0.176
135135
135/150=0.9135/150=0.9
0.176/0.9=0.176/0.9=
0.1960.196
TotalsTotals 8585 150150
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Pre-test Prob = 36%
LR+ =
LR- =
8.2
0.2
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Applying the Test to the Patient
• Is the diagnostic test available, affordable, accurate and precise in our setting?
• Yes
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Applicability (cont’d)
• Test needs to be available, affordable• Interpreted in competent, reproducible
fashion in clinical setting• Potential consequences should justify
the cost
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Applicability (Cont’d)
• Are the study patients similar to our own?
• Are the results applicable to the patient in my practice?
• Will the patient be better off as a result of the test?
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Applicability-study patients’ characteristics
• 235/259 patients had interpretable aspirates• Mean age 79.7, 46% men, 72% had no
medical diagnosis other than anemia• Early dementia 25• CHF 25• COPD 25• Rheumatoid arthritis 17• Osteoarthritis 14• Pneumonia 13
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Can we generate a clinically sensible estimate of our
patient’s pre-test probability?
How can we estimate pre-test probability?
• Clinical experience• Regional or national prevalence statistics• Practice databases• Pretest probability observed in the study itself
• Studies of pre-test probabilities
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Low = 3.6% (2-6)
Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420. utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420.
Risk of PE
Inter = 20%
(17-24)
High = 67%
(54-77)
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Will the post-test probabilities affect our management and
help our patient?
• Could the test result move us across a test-treatment threshold?
• Would the patient be willing to undergo the test?
• Would it help the patient?
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Pre-test Prob = 50%
LR+ =
LR- =
8.2
0.2
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 100%
90% Probability of Fe def Anemia when
Ferritin is <45
10% 90%
x
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Likelihood Ratios for 4 levels of Serum Ferritin
FerritinFerritin Fe def #Fe def # Not Fe defNot Fe def L.R.L.R.
<<1818 4747 22 41.4741.47
>18>18<<4545 2323 1313 3.123.12
>45>45<<100100 7 7 2727 0.460.46
>100>100 88 108108 0.130.13
Total Total 8585 150150
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Calculating Likelihood Ratios
Bone Marrow: Bone Marrow:
iron deficientiron deficient
Bone Marrow: Bone Marrow: normal iron normal iron
Likelihood Likelihood RatiosRatios
Test Results:Test Results:
<< 18 18 4747
47/85=0.55347/85=0.553
22
2/150=0.0132/150=0.013
0.553/0.013=0.553/0.013=
42.542.5
19-4519-45 2323
23/85=0.27123/85=0.271
1313
13/150=0.08713/150=0.087
0.271/0.087=0.271/0.087=
3.113.11
46-10046-100 77
7/85=0.0827/85=0.082
2727
27/150=0.1827/150=0.18
0.082/0.18=0.082/0.18=
0.4560.456
>100>100 88
8/85=0.0948/85=0.094
108108
108/150=0.72108/150=0.72
0.094/0.72=0.094/0.72=
0.1310.131
TotalsTotals 8585 150150
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Clinical Scenario 52 y.o. male admitted to Orthopedics 3 days 52 y.o. male admitted to Orthopedics 3 days
ago for a R femur fracture after falling from a ago for a R femur fracture after falling from a ladderladder
Underwent ORIF 2 days agoUnderwent ORIF 2 days ago Last night developed SOBLast night developed SOB No CP or coughNo CP or cough PE: Afeb 115/70 HR 110 RR 18 95% on 4LPE: Afeb 115/70 HR 110 RR 18 95% on 4L
– Otherwise unremarkable (Lungs clear, No Otherwise unremarkable (Lungs clear, No elevated JVP or RV heave, no lower ext swelling)elevated JVP or RV heave, no lower ext swelling)
Labs: EKG sinus tach, CXR clearLabs: EKG sinus tach, CXR clear D-dimer 0.5 mcg/mL (nl <0.6)D-dimer 0.5 mcg/mL (nl <0.6)
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PICO• P: In a patient with acute onset of SOB,
hypoxia and sinus tachycardia after a major orthopedic surgery for femur fracture
• I: Does a negative D-dimer result• C:• O: Rule out pulmonary embolism• T(ype of question): Diagnosis• T(ype of study): Prospective Cohort
*De Monye W et al: The performance of two rapid d-dimer assays in 287 patients with clinically suspected pulmonary embolism. Thrombosis Res 2002;(107):283-286.
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Low = 3.6% (2-6)
Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420. utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420.
Risk of PE
Inter = 20%
(17-24)
High = 67%
(54-77)
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 20% 100%
Probability of Pulm Embolism
X
5% 90%
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Sensitivity and SpecificitySensitivity and Specificity disease (+) disease (-)
Test (+) 74 77
Test (-) 16 120
Sensitivity (“Positive in disease”) = true pos / all disease = 74 / 90 = 82.2%
Specificity (“Negative in health”) = true neg/all disease free = 120 / 197 = 60.3%
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Likelihood Ratios of D-Dimer TestLikelihood Ratios of D-Dimer Test
disease (+) disease (-)
Test (+) 74 77
Test (-) 16 120
Likelihood ratio (+) = (74 / 90) / (77/197) = 2.1
Likelihood ratio (-) = (16/90) / (120/197) = 0.29
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LR+ =
LR- =
2.1
0.29
Pre-test Prob = 20%
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 5% 100%
Probability of Pulm Embolism if
D-Dimer is negative
X
5% 90%
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LR (using lower cut off 95% LR (using lower cut off 95% sensitive D-Dimer value)sensitive D-Dimer value)
disease (+) disease (-)
Test (+) 86 149
Test (-) 4 48
Likelihood ratio + test = (86/90) / (149/197) = 1.3
Likelihood ratio - test = (4/90) / (48/197) = 0.18
probability of the test result in patients with the diseaseprobability of the same result in patients without diseaseLR =LR =
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LR+ =
LR- =
1.3
0.18
Pre-test Prob = 20%
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Treatment Thresholds
ZONE OF UNCERTAINTYNo Tx Tx
0% 100%
3% Probability of PE if D-Dimer is
negative
3% 90%
x
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Summary
• Develop pre-test probabilities • Steps in appraising a diagnostic test• Calculate and interpret sensitivity,
specificity and likelihood ratios• Evaluate how pre-test probability and
likelihood ratio results affect post-test probability of disease to influence further testing or treatment decisions