SCREENING IN CLINICAL RESEARCH

DR TAN TOH LEONG

SENIOR LECTURER & EMERGENCY PHYSICIAN

MINGGU PENYELIDIKAN KE-18 UKM (2016)

ISSUES IN ASSESSING CLINICAL TESTS

• VALIDITY OF THE TESTS – HOW GOOD IS THE TEST TO IDENTIFY THE

SICK AND THE HEALTHY INDIVIDUALS

• RELIABILITY – HOW STABLE IS THE RESULTS OF THE TEST .

• EFFICIENCY AND COST-EFFECTIVENESS

ISSUES OF MEASUREMENTS

• VALIDITY/ACCURACY

• CONTENT

• CONSTRUCT

• CRITERION

• RELIABILITY/REPRODUCIBILITY

• RANGE

CONTENT VALIDITY

• DEFINITION: THE EXTEND TO WHICH A PARTICULAR METHOD OF

MEASUREMENT INCLUDE ALL OF THE DIMENSIONS OF THE CONSTRUCT ONE

INTENDS TO MEASURE AND NOTHING MORE.

• E.G. A SCALE FOR MEASURING PAIN WOULD HAVE CONTENT VALIDITY IF IT

INCLUDE QUESTIONS ABOUT ACHING, THROBBING, BURNING, AND STINGING

(THE NATURE OF PAIN) BUT NOT ABOUT PRESSURE, ITCHING, NAUSEA,

TINGLING AND THE LIKE.

CONSTRUCT VALIDITY

• DEFINITION: THE PRESENT TO THE EXTEND THAT THE MEASUREMENT IF

CONSISTENT WITH OTHER MEASUREMENTS OF THE SAME PHENOMENON.

• E.G. THE RESEARCHER MIGHT SHOW THAT RESPONSES TO A SCALE

MEASURING PAIN ARE RELATED TO OTHER MANIFESTATIONS OF THE SEVERITY

OF PAIN SUCH AS SWEATING, MOANING, WRITHING, AND ASK FOR PAIN

MEDICINE (THE ASSOCIATED SYMPTOM OF PAIN).

CRITERION VALIDITY

• DEFINITION: THE PRESENT TO THE EXTENT THAT THE MEASUREMENT PREDICT A

DIRECTLY OBSERVABLE PHENOMENON.

• E.G. ONE MIGHT SEE IF RESPONSES ON THE SCALE MEASURING PAN BEAR A

PREDICTABLE RELATIONSHIP TO PAIN OF KNOWN SEVERITY. MILD PAIN FROM

MINOR ABRASION, MODERATE PAIN FROM ORDINARY HEADACHE AND SEVERE

PAIN FROM RENAL COLIC.

RELIABILITY

• DEFINITION: IT IS THE EXTEND TO WHICH REPEATED MEASUREMENTS OF A STABLE

PHENOMENON- BY A DIFFERENT PEOPLE AND INSTRUMENTS, AT DIFFERENT TIMES

AND PLACES AND GET SIMILAR RESULTS.

• OTHER WORD : REPRODUCIBILITY AND PRECISION.

• E.G. THE RELIABILITY OF LABORATORY MEASUREMENTS IS ESTABLISHED BY MEASURE ;

FOR EXAMPLE, THE SAME SERUM OR TISSUE SPECIMEN WITH SOMETIME DIFFERENT

PEOPLE AND WITH DIFFERENT INSTRUMENTS.

• E.G. THE RELIABILITY OF SYMPTOMS CAN BE ESTABLISHED BY SHOWING THAT THEY

ARE SIMILAR DESCRIBE TO DIFFERENT OBSERVERS UNDER DIFFERENT CONDITIONS.

RANGE

• DEFINITION: THE MEASURABLE LEVELS THAT A DEVICE ABLE TO DETECT

• E.G. A INSTRUMENT MAY NOT REGISTER VERY LOW OR HIGH VALUES OF

THE THING BEING MEASURED, LIMITING THE INFORMATION IT CONVEYS.

THUS THE “FIRST GENERATION” METHOD OF MEASURING SERUM

THYROID-STIMULATING HORMONES WAS NOT USEFUL FOR DIAGNOSING

HYPERTHYROIDISM OR FOR PRECISE TITRATE IF THYROXINE

ADMINISTRATION BECAUSE THE METHOD COULD NOT DETECT LOW LEVELS

TSH.

ASSESSING THE VALIDITY AND RELIABILITY OF CLINICAL TEST OR

RESEARCH

HOW TO MEASURE?

• VALIDITY/ACCURACY – SENSITIVITY & SPECIFICITY

• RELIABILITY

• QUALITATIVE

• KAPPA ANALYSIS

• AC-1 ANALYSIS

• QUANTITATIVE

• CROHNBERG ALPHA ANALYSIS

• BLAND-ALTMAN ANALYSIS

SCREENING

• PRESUMPTIVE IDENTIFICATION OF UNRECOGNIZED DISEASE

• USING TEST, EXAMINATION

• CAN APPLY RAPIDLY

• NOT DIAGNOSTIC

• DONE TO APPARENTLY NORMAL WELL PERSON

• USE TO SCREEN RISK FACTORS OR EARLY DISEASE

DIAGNOSTIC VS SCREENING TESTS

• TESTS - HISTORY, PHYSICAL EXAMINATION, QUESTIONAIRE, LAB.

TEST

• DIAGNOSTIC – MAKING DIAGNOSIS AND LEADING TO TREATMENT

• SCREENING – PRESUMPTIVE IDENTIFICATION OF DISEASE OR RISK

FACTORS AMONG APPARENTLY HEALTHY INDIVIDUALS.

STEP BY STEP APPROACH TO SCREENING AND DIAGNOSTIC

RESEARCH.

1. CHOOSE A TOOL: HISTORY TAKING, PHYSICAL EXAMINATION AND

LAB.

2. WE SHOULD KNOW THE “NORMALITY/PARAMETRIC OR NON-

PARAMETRIC” OR CUT-OFF POINT TO CLASSIFY DISEASE & NON-

DISEASE

3. “GOLD STANDARD” – MOST SPECIFIC/ DEFINITIVE OUTCOME

4. DETERMINE THE VALIDITY OF THE TESTS (SENSITIVITY, SPECIFICITY &

PREDICTIVE VALUES.)

TEST FOR NORMALITY

• THE KOLMOGOROV-SMIRNOV TEST, THE ANDERSON-DARLING TEST,

AND THE SHAPIRO-WILK TEST.

• IF THE TEST IS STATISTICALLY SIGNIFICANT (E.G., P<0.05), THEN

DATA DO NOT FOLLOW A NORMAL DISTRIBUTION, AND A

NONPARAMETRIC TEST IS WARRANTED.

WHAT IS NORMALITY

EVEN HARDER TO DEFINE THAN ABNORMALITY, BUT FOLLOWING CHARACTERISTICS USUALLY

PRESENT:

• APPROPRIATE PERCEPTION OF REALITY; REALISTIC IN ASSESSING ACTIONS OF SELF AND

OTHERS AND OWN CAPABILITIES, AND INTERPRETING WHAT IS GOING ON.

• ABILITY TO EXERCISE VOLUNTARY CONTROL OVER BEHAVIOUR; ABLE TO RESTRAIN

(AGGRESSIVE / SEXUAL) URGES - IF FAIL TO CONFORM TO SOCIAL NORMS IT IS A RESULT OF

CHOICE NOT LACK OF CONTROL.

• SELF-ESTEEM AND ACCEPTANCE; COMFORTABLE WITH OTHERS AND CONFIDENT OF SELF

WORTH - FEEL ACCEPTED BY SOCIETY AND VALUED.

• ABILITY TO FORM AFFECTIONATE RELATIONSHIPS; SENSITIVE TO NEEDS OF OTHERS AND NOT

SELF-CENTRED IN THE EXTREME.

• PRODUCTIVITY; HAVE ENERGY AND ENTHUSIASM FOR LIFE.

DEFINING ABNORMALITY

THERE IS NO GENERAL AGREEMENT BUT MOST ATTEMPTS ARE BASED ON ONE OR MORE

(AND USUALLY ALL) OF THE FOLLOWING:

• DEVIATION FROM STATISTICAL NORMS; BASED ON STATISTICAL FREQUENCY, WHERE ABNORMAL IS

STATISTICALLY INFREQUENT. BUT IS EXTREMELY HAPPY ABNORMAL BEHAVIOUR?

• DEVIATION FROM SOCIAL NORMS; NOT FOLLOWING CERTAIN STANDARDS OR NORMS ACCEPTABLE

IN PARTICULAR SOCIETY. BUT CULTURES AND SOCIETIES DIFFER IN WHAT IS NORMAL, AND THE

CONCEPT OF ABNORMALITY CHANGES OVER TIME WITHIN ONE CULTURE.

• MALADAPTIVENESS OF BEHAVIOUR; HAS ADVERSE EFFECTS ON THE INDIVIDUAL AND/OR ON SOCIETY

EG PHOBIAS, ADDICTIONS, EXTREME AGGRESSION ETC).

• PERSONAL DISTRESS; INDIVIDUAL’S SUBJECTIVE FEELINGS OF DISTRESS RATHER THAN BEHAVIOUR.

MOST PEOPLE DIAGNOSED AS MENTALLY ILL ARE ACUTELY MISERABLE.

CUT-OFF POINT?

• FOR ORDINAL/NUMERICAL DATA;

WHEN DOES NORMAL LEAVE OFF AND ABNORMAL BEGINS?

• FOR EXAMPLE;

WHEN DOES A LARGE NORMAL PROSTATE BECOMES TOO LARGE TO BE

CONSIDERED NORMAL?

RECEIVER OPERATING CHARACTERISTIC (ROC), OR ROC CURVE

• AIM TO IMPROVE ‘SIGNAL-TO-NOISE’ RATIO

• USED FOR CHOOSING CUT-OFF POINT FOR CONTINUOUS DATA

• PORTRAYS THE TRADE-OFF BETWEEN IMPROVING EITHER THE SENSITIVITY

OR SPECIFICITY OF A TEST

• SELECT CUT-OFF POINTS AND CALCULATE THE VALUES

• PLOT THE SENSITIVITY (TRUE POSITIVES) AGAINST 1-SPECIFICITY (FALSE

POSITIVES)

1.00

.80

.60

.40

.20

0

Sen

siti

vity

(Tru

e p

osi

tiv

es)

1- specificity

(False positives)

(24)

(27)

(28)

(29)

0 .20 .40 .60 .80 1.00

(21)

ROC curve for mean corpuscular haemoglobin MCH) values

in the screening for thalassaemia carrier (Hasniah et al 2002)

Area = .90

INTERPRETING THE ROC CURVE

• A PERFECT TEST WILL HAVE A

TRUE POSITIVE RATE OF 1.0

AND A FALSE POSITIVE RATE OF

0.0 I.E. A CURVE THAT FILLS THE

SQUARE

Area = 1.00

INTERPRETING THE ROC CURVE

• A NON-INFORMATIVE CURVE

OCCURS WHEN THE TRUE

POSITIVE AND FALSE POSITIVE

RATES ARE EQUAL

Area = 0.50

INTERPRETING THE ROC CURVE

• CHOOSING A CUT-OFF POINT

• THE BEST CUT-OFF WILL BE AT THE POINT WHERE THE CURVE TURNS

• ALSO CONSIDER IMPLICATIONS OF THE TWO POSSIBLE ERRORS (MINIMIZING FALSE +VE OR FALSE NEGATIVE)

• AREA UNDER THE CURVE

• CAN BE USED TO COMPARE TWO TESTS

• A TEST WITH AN ROC CURVE AREA OF 0.90 THE TEST WOULD BE CORRECT 90% OF THE TIME

THE VALIDITY OF A TEST RESULT

DISEASE STATUS

TEST RESULT PRESENT ABSENT

Positive true positive false positive

(TP) (FP)

Negative false negative true negative

(FP) (TN)

SENSITIVITY

• PROBABILITY THAT A SICK INDIVIDUAL WILL BE CLASSIFIED AS SICK

• PROPORTION OF SUBJECTS WITH A DISEASE WHO HAVE A POSITIVE

TEST FOR A DISEASE

SENSITIVITY =

Number of sick people who are

classified as sick

Total number of sick people

Sensitivity = TP

TP + FN X 100 %

SPECIFICITY

• PROBABILITY THAT A HEALTHY INDIVIDUAL WILL BE CLASSIFIED AS HEALTHY

• PROPORTION OF SUBJECTS WITHOUT A DISEASE WHO HAVE A NEGATIVE

TEST

SPECIFICITY =

Number of healthy people who

are classified as healthy

Total number of healthy people

Specificity = TN

TN + FP X 100 %

SENSITIVITY AND SPECIFICITY OF BREAST CANCER SCREENING

BREAST CANCER

CANCER CANCER NOT TOTAL

CONFIRMED CONFIRMED

SCREENING TEST +VE 132 983 1115

PE & MAMMO -VE 45 63650 63695

TOTAL 177 64633 64810

Sensitivity

= 132/177

= 74.6%,

Specificity

= 63650/64633

= 98.5%

SENSITIVITY AND SPECIFICITY OF SCREENING TEST

DISEASE STATUS

POSITIVE NEGATIVE TOTAL

SCREENING TEST +VE A B A + B

-VE C D C + D

TOTAL A + C B + D Sensitivity = A / A + C

Specificity = D / B + D

SENSITIVITY VS SPECIFICITY

•Dangerous but treatable disease (tb, syphilis, Hodgkin)

•early work-up (differential diagnosis)

•discover disease (low prevalence)

•very sensitive test useful when the test negative

•Sn Out

•False positive can harm the patient (cancer)

•to rule in or confirm diagnosis

•very specific test useful when the test positive

•diagnostic test

•Sp In

PREDICTIVE VALUE OF A TEST

• WHETHER OR NOT THE PERSON HAS THE DISEASE, GIVEN THE RESULT

OF THE TEST. WHAT IS THE PROBABILITY ?

• PPV = PROBABILITY OF DISEASE IN PATIENT WITH A POSITIVE TEST

(ABNORMAL)

• NPV = PROBABILITY OF NOT HAVING A DISEASE WHEN THE TEST

NEGATIVE (NORMAL)

• PPV & NPV IS DETERMINED BY PREVALENCE OF DISEASE AND THE

VALIDITY.

PREDICTIVE VALUE OF THE TEST

DISEASE STATUS

POSITIVE NEGATIVE TOTAL

SCREENING TEST +VE A B A + B

-VE C D C + D

TOTAL A + C B + D

PPV = A / A + B

NPV = D / C + D PPV = Prevalence x Sensitivity

(Prev x Sen) + (1 - Sp) (1 - Prev)

PREDICTIVE VALUE OF A TEST

• PPV = THE LIKELIHOOD THAT THE TEST POSITIVE PERSON ACTUALLY HAS A DISEASE

• NPV = THE LIKELIHOOD THAT THE TEST NEGATIVE PERSON ACTUALLY DOES NOT HAVE A DISEASE

• PPV = PREVALENCE X SENSITIVITY

(PREV X SEN) + (1 - PREV)X (1 - SP)

• NPV = (1-PREVALENCE) X SPECIFICITY

(1-PREV) X SP + PREV X (1 - SEN)

PREDICTIVE VALUE OF A TEST • HIGH PPV = SCREENING PERFORMANCE SATISFACTORY

• LOW PPV = THE TEST HAS A POOR SPECIFICITY AND/OR A LOW PREVALENCE

PREVALENCE SENSITIVITY % & SPECIFICITY %

99 95 90 80

99 95 90 80

20 96.1 82.1 69.2 50.0

10 91.7 67.9 50.0 30.8

5 88.9 50.0 32.1 17.4

1 50.0 16.1 8.3 3.9

0.1 9.0 8.7 4.3 2.0

YIELD IN SCREENING

• THE AMOUNT OF PREVIOUSLY UNRECOGNISED DISEASE WHICH IS DIAGNOSED

AND BROUGHT TO TREATMENT (DETECTED) AS A RESULT OF SCREENING. THIS USE

TO MEASURE PROGRAM PERFORMANCE

FACTORS AFFECTING THE YIELD

• SENSITIVITY OF THE TEST

• PREVALENCE OF THE DETECTABLE PRECLINICAL STAGE

• EXTENT OF PREVIOUS SCREENING

• HEALTH BEHAVIOR AND PERCEPTION OF THE DISEASE

CHARACTERISTIC OF DISEASE FOR SCREENING

• FATAL AND PROLONGED MORBIDITY

• MUST HAVE EFFECTIVE TREATMENT (DETECTED STAGE > AFTER SYMPTOM)

• DETECTABLE PRECLINICAL PHASE > PREVALENCE AMONG THE PERSON

SCREENED

CRITERIA FOR SCREENING

• THE CONDITION SHOULD BE IMPORTANT HEALTH PROBLEM

• ACCEPTABLE BY COMMUNITY

• MINIMAL SIDE EFFECTS

• VALIDITY MUST BE SATISFACTORY

• PRESENCE OF GOOD CONFIRMATORY TEST.

• AGREED POLICY ON WHOM TO TREAT

CRITERIA FOR SCREENING

• PRESENCE OF AN EFFECTIVE TREATMENT

• RESOURCES AND FACILITIES FOR TREATMENT

• KNOW THE HISTORY OF PRESENCE ILLNESS

• REASONABLE YIELD

• EVIDENCE THAT THE EARLY DETECTION AND TREATMENT REDUCE MORTALITY AND

MORBIDITY

• THE EXPECTED BENEFIT EXCEED THE RISK OF SCREENING

THANK YOU