10. Diagnostic Test - Ris 07 071107

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STUDY OF DIAGNOSTIC TESTS

Modul Riset


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

- In vivo


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References:- Pusponegoro HD, et al. Uji Diagnostik. In: S.Sastroasmoro & S.Ismael (Ed.). Dasar-dasarMetodologi 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 SRCummings (Eds). Designing a Clinical Research

Baltimore: Williams and Wilkins, 1988.


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

How well a diagnostic test can differentiate presence orabsence of disease.


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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.


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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 : reproducibility4. Epidemiology study


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Structure

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


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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


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Disease status

Breast cancer benign noduleTest result

Positif 65 30

Negative 35 70

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

2x2 table


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Sensitivity

= the proportion of subjects with the disease who havepositive testIndicating how good a test is at identifying the diseased

Specificity= the proportion of subjects without the disease whohave a negative testIndicating how good a test is at indicating thenondiseased


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- 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-)


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Disease status

Breast cancer benign noduleTest result

Positif 65 30

Negative 35 70

True positive : the test is positive & he has the diseaseFalse positive : the test is positive & he doesnt have the disease

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


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DISEASE

YES NO TOTAL

TEST

RESULT

YES TRUE

POSITIVE

FALSE

POSITIVE

TP + FP

NO FALSE

NEGATIVE

TRUE

NEGATIVE

FN + TN

TOTAL TP + FN FP + TN TP + FP + FN +

TN


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GOLD STANDARD

POSITIVE NEGATIVE TOTAL

TEST

RESULT

POSITIVE A

(45)

B

(10)

A + B

(55)

NEGATIVE C

(5)

D

(40)

C + D

(45)

TOTAL A + C(50)

B + D(50)

A + B +C + D

Sensitivity = A : ( A+C) = 90%Specivicity = D : (B + D) = 80%

Positive predictive value = A : (A + B) = 82%Negative predictive value = D : (C + D) = 89%


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Disease status

Breast cancer benign nodule TotalTest result

Positif 70 25 95

Negative 30 75 105

Sensitivity = ?

Specivicity = ?

PV+ = ?

PV- = ?

Total 100 100 200


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Disease status

Breast cancer benign nodule TotalTest result

Positif 70 25 95

Negative 30 75 105

Sensitivity = A : ( A+C) = 70%

Specivicity = D : (B + D) = 75%

PV+ = A : (A + B) = 73.7%

PV- = D : (C + D) = 71.4%

Total 100 100 200


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Steps in diagnostic test research1. Identify why a new diagnostic test is necessary

- How good is the present available diagnostic test? Anyweakness?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


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4. Select gold standard

- Best available diagnostic test5. Do the test

- Blinded6. Data analysis and report

- Sensitivity, Specificity, PV+, PV-.With confidence interval- ROC for continous data


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GOLD STANDARD

- Standard method to determine presence or absenceof disease

- Ideally : always positive for diseased person, andalways 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 thanthe new method.


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Cut Off- When data are in ordinal (categorical) or numeral

(continous) We have to decide the point thatdifferentiate normal and abnormal.

- Depends on the purpose of the test, need highsensitivity or high specificity.

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


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S

ensiti

vit

y

1 - Specificity0 0.2 0.4 0.6 0.8 1.0

0.2

0.6

0.8

0.4

1.0

x

x

x

x

x

Receiver operator curveA graph that show the bargain between sensitivity and specificity when

we determine a cut-off point.Increase sensitivity - decrease specificity, vice versa.

Points closer to diagonal line worse resultSelection of cut-off point depends on the purpose of the test.

A

B

CD


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Receiver operator curve (ROC) for serum alanine aminotransferase (ALT)Level (U/L) in the diagnosis of hepatitis

Sens

itivi

ty

1 - Specificity

0 0.2 0.4 0.6 0.8 1.0

0.2

0.6

0.8

0.4

1.0

x

200

100

25

x

x

400

50


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The value of diagnostic test also depends on prevalence ofthe disease in the population being tested.

Prevalence decreaseless likely that someone with a positive test isactually has the diseasethe more specific a test must be in order to beclinically useful.


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GOLD STANDARD


TEST

RESULT

POSITIVE A

(45)

B

(10)

A + B

(55)

NEGATIVE C

(5)

D

(40)

C + D

(45)

TOTAL A + C(50)

B + D(50)

100

Prevalence = 50%Sensitivity = A : ( A+C) = 90%Specivicity = D : (B + D) = 80%PV+ = A : (A + B) = 82%PV- = D : (C + D) = 89%


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GOLD STANDARD


TEST

RESULT

POSITIVE 18 16 34

NEGATIVE 2 64 66

TOTAL 20 80 100

Prevalence = 20%Sensitivity = A : ( A+C) = 90%

Specivisity = D : (B + D) = 80%Nilai duga positif = A : (A + B) = 55%Nilai duga negatif = D : (C + D) = 97%


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Likelihood ratio

= the likelihood that a person with a disease would havea particular test result devided by the likelihood that aperson without the disease would have that result.

-This especially useful when a test result categorical orcontinous.

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


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Limitations1. Random error

- by chance- quantifiable ---- confidence interval.

2. Systematic error2.1. 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 resulthave already known the outcome of gold standard.

- borderline result --- determine in advance how totreat this result.2.3. Reporting bias

- Unpromising results usually go unreported.------ enough samples, so negative results can be

meaningful and reported.


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Summary1. 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.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.


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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 resultpositive.

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) Identifywhy a new diagnostic test is necessary; b) Determine

the main purpose of the new test; c) Select subjectpopulation; d) Select gold standard; e) Apply the testand the gold standard bilndly; f) Analyse and reportdata in terms of sensitivity, specificity and predictivevalue.


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Thank you

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10. Diagnostic Test - Ris 07 071107

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