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Petch Rawdaree
Assessing diagnostic test Assessing diagnostic test s in Endocrinology s in Endocrinology
Special characteristic of endocrine Special characteristic of endocrine disordersdisorders
Properties of diagnostic testsProperties of diagnostic tests Probability of having diseasesProbability of having diseases Example of diagnostic tests and Example of diagnostic tests and
assessment of the testsassessment of the tests
Petch Rawdaree, MD. MSc, DLSHTMPetch Rawdaree, MD. MSc, DLSHTM
77th th July, 2007July, 2007
Petch Rawdaree
The Endocrine patients The Endocrine patients
General considerations General considerations Special features of endocrine illness Special features of endocrine illness
Discovery through screening Discovery through screening Quantitative rather than qualitative abn Quantitative rather than qualitative abn
ormalitiesormalities Overlap with other diseases Overlap with other diseases Unique features of reproductive disorde Unique features of reproductive disorde
rsrs
Petch Rawdaree
Laboratory testing of endocr Laboratory testing of endocr ine function ine function
Pulsatile hormone secretion Pulsatile hormone secretion Diurnal variation Diurnal variation
Cyclic variation Cyclic variationAgeAge
Sleep entrainment Sleep entrainment Hormone antagonism Hormone antagonism
Dynamic testing Dynamic testing Hormone and metabolite interaction Hormone and metabolite interaction
Protein binding Protein binding Laboratory error Laboratory error
Petch Rawdaree
Evaluation of patients with Evaluation of patients with Endocrine disordersEndocrine disorders
HistoryHistory Details of timingDetails of timing SequenceSequence Changes of diet or avtivityChanges of diet or avtivity Relationship to menstrual cycleRelationship to menstrual cycle Changes in weight or sizeChanges in weight or size Alterations in mood or sleep patternAlterations in mood or sleep pattern Family historyFamily history
Physical examinationPhysical examination GeneralGeneral Targeted examinationTargeted examination
Petch Rawdaree
Attributes of a testAttributes of a test Validity Validity Reliability Reliability Clinical relevance Clinical relevance Feasibility Feasibility CostCost
Petch Rawdaree
Degree to which the data measure Degree to which the data measure what they were intended to measure what they were intended to measure (i.e. the true state of the phenomenon)(i.e. the true state of the phenomenon)
Extent to which repeated Extent to which repeated measurements of a stable phenomenon measurements of a stable phenomenon (by different people, times,places, (by different people, times,places, instruments) get similar resultsinstruments) get similar results
Validity (accuracy)
Reliability (Reproducibility, precision)
Petch Rawdaree
“normal” diseased
false positives
false negatives
Petch Rawdaree
Properties of testProperties of test
SensitivitySensitivity SpecificitySpecificity Predictive value of positive testPredictive value of positive test Predictive value of negative testPredictive value of negative test Likelihood ratio of positive testLikelihood ratio of positive test Likelihood ratio of negative testLikelihood ratio of negative test Pretest probabilityPretest probability Posttest probabilityPosttest probability
Petch Rawdaree
Sensitivity and Sensitivity and SpecificitySpecificity
SensitivitySensitivity=ability of a test to detect the disease =ability of a test to detect the disease among persons who have itamong persons who have it=proportion of people with disease who =proportion of people with disease who have positive testhave positive test
specificityspecificity= ability of a test to confirm normal status = ability of a test to confirm normal status among people without diseaseamong people without disease= proportion of people without disease = proportion of people without disease who have negative test resultwho have negative test result
Petch Rawdaree
Relationship between test’s Relationship between test’s result and truthresult and truth
Disease
Present Absent
Test result
positive True-positive
(a)False-positive
(b)
negativeFalse-negative
(c)True-negative
(d)
a + c b + d
Sensitivity = a/(a+c)Specificity = d/(b+d)
Positive predictive value = a/(a+b)Negative predictive value = d/(c+d)
Prevalence = (a+c)/(a+b+c+d)Odds = (a+c)/(b+d)
Petch Rawdaree
Test result in primary care Test result in primary care settingsetting
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh99 99
(a)(a)
9999
(b)(b)
normalnormal11
(c)(c)
98019801
(d)(d)
100100 99009900
Sensitivity = 99/(99+1)=99%Specificity = 9801/(99+9801)=99%
PPV = 99/(99+99)=50%NPV = 9801/(9801+1)=100%
Prevalence = (a+c)/(a+b+c+d)=1%Odds = (a+c)/(b+d)=100/9900=1:99
N= 10,000
Petch Rawdaree
Test results in an Test results in an endocrinologist’s officeendocrinologist’s office
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh 990990
(a)(a)
9090
(b)(b)
normalnormal1010
(c)(c)
89108910
(d)(d)
10001000 90009000
Sensitivity = 990/(990+10)=99%Specificity = 8910/(90+8910)=99%
PPV = 990/(990+90)=91.6%NPV = 8910/(10+8910)=99.9%
Prevalence = (a+c)/(a+b+c+d)=10%Odds = (a+c)/(b+d)=1:9
N= 10,000
Petch Rawdaree
Relationship wetween UAER ( gold Relationship wetween UAER ( gold standard) and UACR(test) and two standard) and UACR(test) and two
levels of test’s resultslevels of test’s results UAER
> 28.8mg/d < 28.8mg/d
UACR> 15 mg/g 69 14
< 15 mg/g 0 40
69 54
Sensitivity = 69/(69+0)=100%Specificity = 40/(14+40)=74%
Positive PV = 69/(69+14)=83.1%Negative PV = 40/(0+40)=100%
Prevalence = (a+c)/(a+b+c+d)=56%Odds = (a+c)/(b+d)=69:54
N= 123
Petch Rawdaree
Relationship between UAER(gold Relationship between UAER(gold standard) and UACR(test) and two standard) and UACR(test) and two
levels of test’s resultslevels of test’s resultsUAERUAER
> > 28.8mg/28.8mg/
dd
< < 28.8mg/28.8mg/
dd
UACRUACR
> 26.8 > 26.8 mg/gmg/g 6161 66
< 26.8 < 26.8 mg/gmg/g 88 4848
6969 5454
Sensitivity = 61/(61+8)=88.4%Specificity = 48/(6+48)=88.9%
PPV = 61/(61+6)=91%NPV = 48/(8+48)=85.7%
Prevalence = (a+c)/(a+b+c+d)=56%Odds = (a+c)/(b+d)=69:54
N= 123
Petch Rawdaree
Relationship between prevalence Relationship between prevalence of disease, sensitivity, specificity, of disease, sensitivity, specificity,
and predictive valueand predictive value
DiseaseDisease
PresenPresentt
AbsentAbsent
Test Test resultresult
+ ve+ ve a a 2b2b
- veve c c 2d 2d
a + ca + c 2(b + d)2(b + d)
Petch Rawdaree
Sensitivity and specificity Sensitivity and specificity do not answer clinical do not answer clinical
questions:questions: If a patient’s test result is positive, If a patient’s test result is positive,
what is the probability that he or she what is the probability that he or she has the disease being tested?has the disease being tested?
If the result is negative, what is the If the result is negative, what is the probability that the patient does not probability that the patient does not have the disease?have the disease?
Petch Rawdaree
Predictive value of testPredictive value of test Predictive value of positive testPredictive value of positive test
= probability of the person having the = probability of the person having the disease when the test is positivedisease when the test is positive= proportion of the subjects who had = proportion of the subjects who had positive test results had the diseasepositive test results had the disease
Predictive value of negative testPredictive value of negative test= probability of the person not having = probability of the person not having disease when the test is negativedisease when the test is negative= proportion of the subject who had = proportion of the subject who had negative test results were free of the negative test results were free of the diseasedisease
Petch Rawdaree
Test result in primary care Test result in primary care settingsetting
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh99 99
(a)(a)
9999
(b)(b)
normalnormal11
(c)(c)
98019801
(d)(d)
100100 99009900
Sensitivity = 99/(99+1)=99%Specificity = 9801/(99+9801)=99%
PPV = 99/(99+99)=50%NPV = 9801/(9801+1)=100%
Prevalence = (a+c)/(a+b+c+d)=1%Odds = (a+c)/(b+d)=100/9900=1:99
N= 10,000
Petch Rawdaree
Test results in an Test results in an endocrinologist’s officeendocrinologist’s office
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh 990990
(a)(a)
9090
(b)(b)
normalnormal1010
(c)(c)
89108910
(d)(d)
10001000 90009000
Sensitivity = 990/(990+10)=99%Specificity = 8910/(90+8910)=99%
PPV = 990/(990+90)=91.6%NPV = 8910/(10+8910)=99.9%
Prevalence = (a+c)/(a+b+c+d)=10%Odds = (a+c)/(b+d)=1:9
N= 10,000
Petch Rawdaree
ValidityValidity
In a clinical settingIn a clinical setting
Likelihood ratio (LR) better
LR= Probability of result in diseased people Probability of result in non-dis. people
In tests measuring dicotomous variables (i.e.yes/no)
LR+ = Sensitivity/(1-Specificity)LR- = (1-Sensitivity)/Specificity
Petch Rawdaree
Likelihood ratiosLikelihood ratios Likelihood ratio positive (LR+)Likelihood ratio positive (LR+)โอกาสที่� โอกาสที่� test test จะให้�ผล บวก ในคนที่�เป็�นโรค เที่�ยบ ก�บคนที่�ไม่�เป็�นโรคจะให้�ผล บวก ในคนที่�เป็�นโรค เที่�ยบ ก�บคนที่�ไม่�เป็�นโรค
= sensitivity/false-positive= sensitivity/false-positive= sensitivity/(1-specificity)= sensitivity/(1-specificity)
““The higher ratio (>1) , the better the test”The higher ratio (>1) , the better the test”
Likelihood ratio negative (LR –)Likelihood ratio negative (LR –)โอกาสที่� โอกาสที่� test test จะให้�ผล ลบ ในคนที่�เป็�นโรค เที่�ยบก�บ คนที่�ไม่�เป็�นโรคจะให้�ผล ลบ ในคนที่�เป็�นโรค เที่�ยบก�บ คนที่�ไม่�เป็�นโรค
= false-negative/specificity= false-negative/specificity= (1-sensitivity)/specificity= (1-sensitivity)/specificity
““The smaller ratio ( close to 0 ), the better the test”The smaller ratio ( close to 0 ), the better the test”““no effect of prevalence on likelihood no effect of prevalence on likelihood
ratios”ratios”
Petch Rawdaree
Likelihood ratiosLikelihood ratios
Disease
Present Absent
Test result
positive True-positive
(a)False-positive
(b)
negativeFalse-negative
(c)True-negative
(d)
a + c b + d
Sensitivity = a/(a+c)Specificity = d/(b+d)
LR+ = [a/(a+c)]/[b/(b+d)LR- = [c/(a+c)/d(b+d)]
Prevalence = (a+c)/(a+b+c+d)Odds = (a+c)/(b+d)
Petch Rawdaree
Test results in an Test results in an endocrinologist’s officeendocrinologist’s office
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh 990990
(a)(a)
9090
(b)(b)
normalnormal1010
(c)(c)
89108910
(d)(d)
10001000 90009000
Sensitivity = 990/(990+10)=99%Specificity = 8910/(90+8910)=99%
LR+ = [990/(990+10)]/[90/(90+8910)=99LR- = [10/(990+10)/[8910/(90+8910)]=0.01
Prevalence = (a+c)/(a+b+c+d)=10%Odds = (a+c)/(b+d)=1:9
N= 10,000
Petch Rawdaree
Test results in an Test results in an endocrinologist’s officeendocrinologist’s office
hypothyroidismhypothyroidism
PresentPresent AbsentAbsent
TSH resultTSH result
highhigh 990990
(a)(a)
9090
(b)(b)
normalnormal1010
(c)(c)
89108910
(d)(d)
10001000 90009000
Sensitivity = 990/(990+10)=99%Specificity = 8910/(90+8910)=99%
LR+ = [990/(990+10)]/[90/(90+8910)=99LR- = [10/(990+10)]/[8910/(90+8910)]=0.01
Prevalence = (a+c)/(a+b+c+d)=10%Odds = (a+c)/(b+d)=1:9
N= 10,000
Petch Rawdaree
Interpretation of Likelihood Interpretation of Likelihood RatiosRatios
Likelihood ratio +Likelihood ratio +The higher, the betterThe higher, the better LR+ >10 conclusive LR+ >10 conclusive
changes from pre- to changes from pre- to post-test probabilitypost-test probability
5-10 moderate shift5-10 moderate shift 2-5 small changes in 2-5 small changes in
probabilityprobability 1-2 rarely important 1-2 rarely important
changeschanges
Likelihood ratio –Likelihood ratio –Closing to 0 is betterClosing to 0 is better LR- <0.1 conclusive LR- <0.1 conclusive
changes from pre- to changes from pre- to post-test probabilitypost-test probability
0.1-0.2 moderate 0.1-0.2 moderate shiftshift
0.2-0.5 small changes 0.2-0.5 small changes in probabilityin probability
0.5-1 rarely 0.5-1 rarely important changesimportant changes
Petch Rawdaree
Likelihood ratios for the diagnosis of Likelihood ratios for the diagnosis of malignancy in euthyroid patients with a single malignancy in euthyroid patients with a single
or dominant thyroid noduleor dominant thyroid nodule
Prevalence (pretest probability)(%)
No. of patients included
Test Result LR(95%CI)
20 132 FNAB guided with U/S
Malignant 226(4.4-11.7)
Suspicious 1.3 (0.52-3.2)
Insufficient
2.7 (0.52-15)
benign 0.24 (0.11-0.52)
7-22 868 FNAB not guided
Malignant 34 (15-74)
Suspicious 1.7 (0.94-3)
Insufficient
0.5 (0.27-0.76)
benign 0.23 (0.13-0.42)
Petch Rawdaree
Characteristics of laboratory Characteristics of laboratory tests in thyroid disorderstests in thyroid disorders
testtest SeSe SpSp LRLR++
LRLR--
hyperthyroidismhyperthyroidism
Total TTotal T44 90.90.00
90.90.00
9.09.0 0.10.111
TT33 RIA RIA 96.96.00
96.96.00
24.24.00
0.00.044
TSHTSH 99.99.00
99.99.00
99.99.00
0.00.011
Primary hypothyroidismPrimary hypothyroidism
Total TTotal T44 90.90.00
85.85.00
6.06.0 0.10.122
TT33 RIA RIA 95.95.00
95.95.00
19.19.00
0.00.055
TSHTSH 99.99.00
99.99.00
99.99.00
0.00.011
Petch Rawdaree
Example: calculation LRs Example: calculation LRs from Sensitivity and from Sensitivity and
specificityspecificity LR+ LR+
=[sensitivity]/[false positive error]=[sensitivity]/[false positive error]
= [sensitivity]/[1-specificity]= [sensitivity]/[1-specificity]
=90/[100-85]=90/[100-85]
=90/15 = 6=90/15 = 6 LR-LR-
=[false negative error] /[specificity]=[false negative error] /[specificity]
=[100-90]/85=[100-90]/85
=10/85 = 0.12=10/85 = 0.12
Petch Rawdaree
Characteristics of laboratory Characteristics of laboratory tests in pheochromocytomatests in pheochromocytoma
testtest SeSe SpSp LR+LR+ LR-LR-
Urine VMAUrine VMA 42.42.00
99.99.00
42.42.00
0.50.599
Urine metanephrinesUrine metanephrines 79.79.00
93.93.00
11.11.33
0.20.233
Plasma normetanephrine Plasma normetanephrine >0.66 nmol/L >0.66 nmol/L
or metanephrine > 0.30 or metanephrine > 0.30 nmol/lnmol/l
100100.0.0
85.85.00
6.76.7 0.00.0
Colnidine suppression testColnidine suppression test 98.98.22
97.97.22
35.35.11
0.00.022
Plasma catecholamine after Plasma catecholamine after supine 30 min.supine 30 min.
94.94.00
97.97.00
31.31.33
0.00.066
Petch Rawdaree
Characteristics of tests for Characteristics of tests for thyroid nodulethyroid nodule
TestTest SeSe SpSp LR+LR+ LR-LR-
Thyroid nodule (benign vs. mal.)Thyroid nodule (benign vs. mal.)
Local painLocal pain 33 9494 0.50.5 1.01.0
Hard to palpationHard to palpation 4242 8989 3.83.8 0.540.54
Fix to surrounding tissueFix to surrounding tissue 3131 9494 5.25.2 0.730.73
Cold nodule on iodine131Cold nodule on iodine131 8383 2525 1.11.1 0.680.68
Solid or mixed lesion on Solid or mixed lesion on ultrasoundultrasound
9595 1818 1.21.2 0.280.28
No change in size after T4 No change in size after T4 suppressionsuppression RxRx
8585 2525 1.11.1 0.60.6
FNBA: positive for malignancyFNBA: positive for malignancy -- -- 74.074.0 --
FNBA: suspiciousFNBA: suspicious -- -- 1.21.2 --
FNBA: benignFNBA: benign 0.090.09 --
Petch Rawdaree
Characteristics of tests for Characteristics of tests for Cushing’s syndromeCushing’s syndrome
TestTest SeSe SpSp LR+LR+ LR-LR-
Cushing’s syndromeCushing’s syndrome
Plasma cortisol 8.00 am >13-20 Plasma cortisol 8.00 am >13-20 ug/100mlug/100ml
83.083.0 67.067.0 2.52.5 0.160.16
Plasma cortisol midnight > 6-15 Plasma cortisol midnight > 6-15 ug/mlug/ml
96.096.0 96.096.0 24.024.0 0.040.04
24-hr urine free cortisol >20-181 24-hr urine free cortisol >20-181 ug/dayug/day
94.094.0 91.091.0 10.010.0 0.070.07
Low-dose dexamethasone Low-dose dexamethasone suppression: urine free cortisol > suppression: urine free cortisol > 0.019-0.025mg/day0.019-0.025mg/day
95.095.0 97.097.0 32.032.0 0.050.05
Cushing’s diseaseCushing’s disease
High-dose dexa- suppression testHigh-dose dexa- suppression test
Urine free cortisol suppressed > Urine free cortisol suppressed > 50%50%
90.090.0 79.079.0 4.34.3 0.130.13
High-dose dexa- suppression testHigh-dose dexa- suppression test
Urine free cortisol suppressed > Urine free cortisol suppressed > 80%80%
81.081.0 92.092.0 10.110.1 0.210.21
Petch Rawdaree
Prevalence (probability) Prevalence (probability) ≈ Odds≈ Odds
probaprobabilitybility
PrevalePrevalence (%)nce (%)
DiseasDiseasee
Total Total populatiopopulatio
nn
No No diseasedisease OddsOdds
0.20.2 2020 2020 100100 8080 0.250.25
0.10.1 1010 1010 100100 9090 0.110.11
0.050.05 55 55 100100 9595 0.05260.0526
0.010.01 11 11 100100 9999 0.0100.010
0.0010.001 0.10.1 11 1,0001,000 999999 0.00100.001000
Petch Rawdaree
Probability of having Probability of having diseasedisease
Pre-test probabilityPre-test probability= prevalence of disease= prevalence of disease
≈ ≈ pre-test odds of diseasepre-test odds of disease Post-test probabilityPost-test probability=probability of disease if test is positive=probability of disease if test is positive
≈ ≈ post-test odds of disease if test is post-test odds of disease if test is positivepositive
= Pre-test odds of disease = Pre-test odds of disease ×× LR+ LR+
Petch Rawdaree
Calculation of post-test Calculation of post-test probabilityprobability
Post-test probabilityPost-test probability≈ ≈ post-test odds of disease if test is positivepost-test odds of disease if test is positive
= Pre-test odds of disease = Pre-test odds of disease ×× LR+ LR+
ExampleExample: if LR+ = 8 : if LR+ = 8 Prevalence = 20% Prevalence = 20% pre-test odds = 20/80 = pre-test odds = 20/80 =
1:4 1:4
Post-test odds = 1:4 x 8 = 8:4Post-test odds = 1:4 x 8 = 8:4
post-test probability = 8/(8+4) = 66.6 %post-test probability = 8/(8+4) = 66.6 %
Petch Rawdaree
Calculation of post-test Calculation of post-test probability of diseaseprobability of disease
1.1. Find the symptom, Find the symptom, disease and test of disease and test of interestinterest
2.2. Estimate the probability Estimate the probability of disease before testingof disease before testing
3.3. Convert the probability of Convert the probability of disease to an odds of disease to an odds of diseasedisease
4.4. Multiply the pre-test odds Multiply the pre-test odds by the likelihood ratioby the likelihood ratio
5.5. Covert the post-test odds Covert the post-test odds to a post-test probabilityto a post-test probability
1.1. Hypothyroidism: TSH Hypothyroidism: TSH levellevel
2.2. Pretest probability = Pretest probability = 20%20%
3.3. Odds of hypothyroidism Odds of hypothyroidism = 20:80 = 1:4 = 20:80 = 1:4
4.4. LR+ for TSH in LR+ for TSH in hypothyroidism = 99 hypothyroidism = 99 1:4 x 99 = 99:4 1:4 x 99 = 99:4
5.5. 99/(99+4) = 96%99/(99+4) = 96%
Petch Rawdaree
How can we improve How can we improve accuracy of our diagnosisaccuracy of our diagnosis
Seek for other evidence Seek for other evidence supporting the diagnosissupporting the diagnosis Increase pre-test probabilityIncrease pre-test probability
Other diagnostic tests which Other diagnostic tests which have more sensitivity/specificity have more sensitivity/specificity and higher predictive value of and higher predictive value of positive testpositive test
Gold standard diagnostic testGold standard diagnostic test
Petch Rawdaree
conclusionsconclusions Clinical diagnosis is fundamental is endocrine Clinical diagnosis is fundamental is endocrine
disordersdisorders Selection of appropriate tests guided by tests Selection of appropriate tests guided by tests
propertiesproperties Diagnosis is integration of clinical experiences Diagnosis is integration of clinical experiences
and tests interpretationsand tests interpretations
Suggest reading: Suggest reading:
Endocrinology and Metabolism Clinics of Endocrinology and Metabolism Clinics of North North America: vol 26 No 1 March 1999America: vol 26 No 1 March 1999
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