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STUDY OF DIAGNOSTIC TESTS

T. Mirawati Sudiro Dept. Microbiology FKUI

Laboratory study :
- Evaluation of diagnostic tests - Experimental study : - In vitro - In vivo

References:
- Pusponegoro HD, et al. Uji Diagnostik. In: S. Sastroasmoro & S.Ismael (Ed.). Dasardasar Metodologi penelitian klinis. Edisi ke-2. Jakarta: CV Sagung Seto, 2002. - Warren S, et al. Designing a New Study III: Diagnostic Test. In: SB Hulley and SR Cummings (Eds). Designing a Clinical Research Baltimore: Williams and Wilkins, 1988.

QUESTIONS Is RT-PCR useful in the diagnosis of dengue infection? Among patients with hypertension, is a serum creatinin level useful in the diagnosis of renovascular disease? How good USG can predict breast cancer in patients with breast tumor?

How well a diagnostic test can differentiate presence or absence of disease.

Purpose of diagnostic tests :


1. Diagnosis or exclusion of disease - The tests must be : sensitive and specific 2. Screening of disease among asymptomatic persons. Additional test will be needed to confirm early diagnosis. The test are useful when: - Prevalence of disease is high - Significant morbidity/mortality without treatment - Effective therapy is available - Early treatment gives better outcome.

Purpose of diagnostic test (contd.)


3. Part of the treament - To monitor disease/ treatment progress - To identify complication ` - To monitor drug level - Determine prognosis - To confirm indeterminate tests. - Characterization of causative microorganism (e.g. drug resistance, genotype) Important : reproducibility 4. Epidemiology study

Structure
They have : - Predictor variable (the test results) - Outcome variable (presence or absence of disease)

The test results as the predictor variable

- dichotomous (positive or negative) - categorical (++++, +++, ++, + or -) - continous ( . Mg of glucose/ ml) --- cut off point

The disease as outcome variable


- Absence or presence of disease - Determined by gold standard

2x2 table
Disease status

Test result
Positif Negative

Breast cancer
65 35

benign nodule
30 70

Analysis with x2 p< 0.001 Statistically the positive result is highly correlated with presence of disease. But this test cannot well differentiate absence or presence of disease.

Sensitivity

= the proportion of subjects with the disease who have positive test Indicating how good a test is at identifying the diseased

Specificity

= the proportion of subjects without the disease who have a negative test Indicating how good a test is at indicating the nondiseased

- The probability that a person with a positive result actually has the disease. ------

Positive predictive value (PV+)

- The probability that a person with a negative result actually doesnt have the disease

------

Negative predictive value (PV-)

Disease status

Test result
Positif

Breast cancer
65

benign nodule
30

Negative

35

70

True positive : the test is positive & he has the disease False positive : the test is positive & he doesnt have the disease True negative :The test is negative & doesnt have the disease False negative : The test is negative & he has the disease

DISEASE

YES

NO

TOTAL

TEST RESULT

YES NO

TRUE POSITIVE FALSE NEGATIVE

FALSE POSITIVE TRUE NEGATIVE

TP + FP FN + TN

TOTAL

TP + FN

FP + TN

TP + FP + FN + TN

GOLD STANDARD POSITIVE TEST RESULT POSITIVE A (45) NEGATIVE B (10) TOTAL A+B (55)

NEGATIVE
TOTAL

C (5)
A+C (50)

D (40)
B+D (50)

C+D (45)
A+B+ C+D

Sensitivity = Specivicity = Positive predictive value = Negative predictive value =

A : ( A+C) D : (B + D) A : (A + B) D : (C + D)

= = = =

90% 80% 82% 89%

Disease status
Test result Positif Negative

Breast cancer
70 30

benign nodule
25 75

Total
95 105

Total

100

100

200

Sensitivity

= ?

Specivicity
PV+ PV-

= ?
= ? = ?

Disease status
Test result Positif Negative

Breast cancer
70 30

benign nodule
25 75

Total
95 105

Total

100

100

200

Sensitivity Specivicity PV+ PV-

= A : ( A+C) = D : (B + D) = A : (A + B) = D : (C + D)

= 70% = 75% = 73.7% = 71.4%

Steps in diagnostic test research

1. Identify why a new diagnostic test is necessary - How good is the present available diagnostic test? Any weakness? Can a new method overcome the weakness of the old one? 2. Determine the main purpose of the new test. - To screen? --- high sensitivity - To confirm diagnosis? --- high sensitivity and specificity - To exclude? ---- high specificity

3. Select subject population. - Screening / Case finding/ Diagnosis - Location - Sample number - Inclusion criteria 4. Select gold standard - Best available diagnostic test 5. Do the test - Blinded 6. Data analysis and report - Sensitivity, Specificity, PV+, PV-. With confidence interval - ROC for continous data

GOLD STANDARD
- Standard method to determine presence or absence of disease - Ideally : always positive for diseased person, and always negative for non-diseased person ---- rare, if any ----- use the best method available - One or combination of methods

- Its sensitivity and specificity should not lower than the new method.

Cut Off
- When data are in ordinal (categorical) or numeral (continous) We have to decide the point that differentiate normal and abnormal. - Depends on the purpose of the test, need high sensitivity or high specificity.

- E.g : for screening : high sensitivity.To decide whether a patient need a high-risk surgery : high specificity.

1.0 S e n s i t i v i t y C 0.8

0.6

0.4 0.2

A
x

0.2

1 - Specificity

0.4

0.6

0.8
x

1.0

Receiver operator curve A graph that show the bargain between sensitivity and specificity when we determine a cutx off point. Increase sensitivity decrease specificity, vice versa. Points closer to diagonal line worse result Selection of cut-off point depends on the purpose of the test.

Receiver operator curve (ROC) for serum alanine aminotransferase (ALT) Level (U/L) in the diagnosis of hepatitis
S 1.0 e n 0.8 s i 0.6 t i v 0.4 i t y 0.2
25
50

100

200

400

0.2

0.4

0.6

0.8

1.0

1 - Specificity

The value of diagnostic test also depends on prevalence of the disease in the population being tested.
Prevalence decrease less likely that someone with a positive test is actually has the disease the more specific a test must be in order to be clinically useful.

GOLD STANDARD
POSITIVE NEGATIVE TOTAL

TEST RESULT

POSITIVE
NEGATIVE

A (45)
C (5)

B (10)
D (40)

A+B (55)
C+D (45)

TOTAL

A+C (50)

B+D (50)

100

Prevalence = 50% Sensitivity Specivicity PV+ PV-

= = = =

A : ( A+C) D : (B + D) A : (A + B) D : (C + D)

= = = =

90% 80% 82% 89%

GOLD STANDARD

POSITIVE
TEST RESULT POSITIVE NEGATIVE TOTAL 18 2 20

NEGATIVE
16 64 80

TOTAL
34 66 100

Prevalence = 20% Sensitivity Specivisity Nilai duga positif Nilai duga negatif

= = = =

A : ( A+C) D : (B + D) A : (A + B) D : (C + D)

= = = =

90% 80% 55% 97%

Likelihood ratio
= the likelihood that a person with a disease would have a particular test result devided by the likelihood that a person without the disease would have that result. -This especially useful when a test result categorical or continous. Positive Likelihood ratio = a/(a+c) : b/(b+d) = sensitivity : (1-specificity) Negative Likelihood ratio = c/(a+c) : d/(b+d) = (1-sensitivity) : specificity

Limitations
1. Random error - by chance - quantifiable ---- confidence interval.

2. Systematic error
2.1. Sampling bias : - When thestudy sample is not representative of the target population in which test will be used.

2.2. Measurement bias : - Increase when the person determine the test result have already known the outcome of gold standard. - borderline result --- determine in advance how to treat this result. 2.3. Reporting bias - Unpromising results usually go unreported. ------ enough samples, so negative results can be meaningful and reported.

Summary
1. A diagnostic test study determines the usefulness of a test in the diagnosis of a disease. Good tests are those that distinguish the diseased from the non-diseased, and are safe, quick, simple, painless, reliable, and inexpensive. Randomized blinded trial and usual clinical practice as model is important in diagnostic test study.

Summary
2. In diagnostic test study there is a predictor variable (test result) and an outcome variable (the disease, determined by gold standard). The goal is to describe how strong the association is, in terms of its sensitivity and specificity. 3. The investigator should determine the sensitivity, specificity, predictive value of positive test, predictive value of negative test. A cutoff point must be determined for calling a result positive.

Summary
4. Studies of diagnostic tests are subject to several biases; the most important are sampling bias, measurement bias, and reporting bias. 5. Steps in planning diagnostic test study : a) Identify why a new diagnostic test is necessary; b) Determine the main purpose of the new test; c) Select subject population; d) Select gold standard; e) Apply the test and the gold standard bilndly; f) Analyse and report data in terms of sensitivity, specificity and predictive value.

Thank you

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