אבחנה וסריקה diagnostic and screening tests

ד"ר רונית קלדרון-מרגלית

Screening vs. Diagnosisscreening

negative positive

diagnosis

No disease

Havedisease

treatment

Clean separation of normal from abnormal people. Assay for reduced glutathione in male relatives of patients with glucose 6-phosphate dehydrogenase

deficiency

Separating normal from abnormal when few of the patients are abnormal. Hypothetical distribution of

serum calciums in normal and hyperparathyroid people in the general population (prevalence of

normal/prevalence of hyperparathyroid 200/1)

Change in normal function with age. BUN people aged 20-29 and 80 or older

The relationship between normal and the risk of disease. The risk for men having gouty arthritis at various levels of serum

uric acid

Increasing risk through the normal range. Serum cholesterol and the risk of coronary heart disease in

men aged 30-39.

Percentage distribution of serum cholesterol levels (mmol/L) in men aged 50-62 who did or did not subsequently develop coronary heart disease

Increasing number of procedures per patient at the Ohio State University Hospitals, Columbus, Ohio

Percentage of persons expected to be normal for a number of test, each using x ± 2s normal range

Number of different tests Persons expected to be normal for all tests undertaken (%)

1 2 3 4 5 6 7 8 9 10 11 12

95.45 91.11 86.96 83.00 79.23 75.62 72.18 68.90 65.76 62.77 59.91 57.19

התבחין: תוקף ומהימנותValidity and reliability

A high reliability mean that in repeated measurements the results fall very close to each other; conversely, a low reliability means that they are scattered. Validity determines how close the mean of repeated measurements is to the true value. A low validity will produce more problems when interpreting results than a low reliability

Different combinations of high and low precision/reliability and validity

תוקף נמדד ע"י מידת הדיוק של התבחין: – עד כמה התבחין רגיש sensitivityרגישות - •

לזהות את החולים – עד כמה התבחין סגולי specificityסגוליות - •

בזיהוי הבריאים

עבור השימוש הקליני:

positive predictive value– ערך ניבוי חיובי

negative predictive value– ערך ניבוי שלילי

הערכת תוקף

Disease

PresentAbsent

Test

AbnormalTrue positive

False positive

NormalFalse negative

True negative

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Sensitivity = a/(a+b)

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Specificity = d/(c+d)

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Accuracy = (a+d)/(a+b+c+d)

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Positive predictive value = the probability of an individual with an abnormal result to have the disease = a/(a+c)

Disease

PresentAbsent

Test

AbnormalTrue positive

a

False positive

c

NormalFalse negative

b

True negative

d

Negative predictive value = the probability of an individual with a normal result to be free of disease = d/(b+d)

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Prevalence = pretest likelihood of disease =prior probability of disease = 230/2300=10%

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Sensitivity= TP rate =215/230=93%

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Specificity= TN rate =1822/2070= 88%

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Positive Predictive Value= ppv=predictive value of a positive test=posttest likelihood or posterior probability of disease= 215 / 463 = 46%

MINo MI

CK test results

Positive

(>80IU)

215248463

Negative(<80 IU)

1518221837

23020702300

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Negative Predictive Value= npv=predictive value of a negative test=posttest likelihood or posterior probability of no disease= 1822 / 1837 =99%

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Prevalence = pretest likelihood of disease =prior probability of disease = 230/360=64%

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Sensitivity= TP rate =215/230=93%

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Specificity= TN rate =114/130= 88%

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among general hospital admissions

Positive Predictive Value= ppv=predictive value of a positive test=posttest likelihood or posterior probability of disease= 215 / 231 = 93%

MINo MI

CK test results

Positive

(>80IU)

21516231

Negative(<80 IU)

15114129

230130360

The sensitivity, specificity and predictive values of the CK test in myocardial infarction

among coronary care unit admissions

negative Predictive Value= npv=predictive value of a negative test=posttest likelihood or posterior probability of no disease= 114 / 129 = 88%

Positive predictive value according to sensitivity, specificity, and prevalence of

disease

Effect of prevalence on predictive value: positive predictive value of prostatic acid phosphatase for

prostatic cancer (sensitivity=70%, specificity=90%) in various clinical settings

Setting Prevalence Positive predictive value

cases/100,000 %

General population 35 0.4

Men, age 75 or greater 500 5.6

Clinically suspicious

prostatic nodule 50,000 93.0

בעוד שרגישות וסגוליות הן מאפיינים של •הבדיקה,

ערכי הניבוי החיובי והשלילי תלויים גם במרכיב האוכלוסייה - בהמצאות המחלה באוכלוסיה

הנבדקת

The relation between sensitivity and specificity

רגישות גבוהה

• Don’t want to miss cases:– Severe disease– Effective treatment

• Don’t want to falsely label people as ill:– Fatal, no effective treatment– Emotional burden, stigma

סגוליות גבוהה

ROC curves for serum creatinine phosphokinase as used to detect myocardial infarction (hypothetical data)

Copyright restrictions may apply.

Ullrich, C. et al. JAMA 2005;294:924-930.

Receiver Operating Characteristic Curves for Reticulocyte Hemoglobin Content and Hemoglobin for the Detection of Iron Deficiency at Initial Screening

Hb=11.0

26.7

Triple test: serum α-fetoprotein, unconjugated

estriol, and human chorionic gonadotropin in

the 2nd trimester. Quadruple test: Triple test+

inhibin A. Combined test: serum pregnancy-associated

plasma protein A, free β subunit of human

gonadotropin, and nuchal translucency in the 1st

trimester. Integrated test: Combined

test+ Quadruple test

From Nelson textbook, based on Wald NJ, et al. NEJM 1999; 341:461–7From Nelson textbook, based on Wald NJ, et al. NEJM 1999; 341:461–7

Screening for Down’s syndrome

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91%

A. 90% clinical probability

Coronary Disease

+ - T

+ 540 9 549 PPV 98%

Exercise - 360 91 451 NPV 20%

ECG

T 900 100 1000

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91% cont.

B. 5% Clinical probability

+ - T

+ 30 86 116 PPV 26%

Exercise - 20 864 884 NPV 98%

ECG T 50 950 1000

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91% cont.

C. 50% Clinical probability

+ - T

+ 300 45 345 PPV 87%

Exercise- 400 445 655 NPV 69%

ECG T 500 500 1000

רמות המניעה

מניעה ראשונית: פעולות שמטרתן למנוע •התפתחותה של מחלה

מניעה שניונית: התערבויות מוקדמות במהלך •המחלה שמטרתן ריפוי/שינוי מהלך המחלה.

מניעה שלישונית: התערבויות במהלך מחלה •קלינית שמטרתן שיקום/שיפור איכות החיים.

מהי סריקה?

רציונאל

אבחנה מוקדמת של מחלה תוביל לטיפול מוקדם •ולכן לעליה בסיכוי לריפוי והארכת חיים

Disease onset symptoms diagnosis

Clinical outcome, e.g.

death/disability

detection death

Natural course

screening

Time

הנחות יסוד

קיים שלב במהלך המחלה שבו טיפול יעיל •יותר מאשר לאחריו

עבור כל או רוב החולים ישנה תקופה •אסימפטומטית שבה ניתן לאבחן את המחלה

עבור רוב או כל החולים השלב הפרהקליני •יעבור להיות קליני בהיעדר טיפול

מהי סריקה?

איתור מוקדם של מחלה•

שלב א-סימפטומטי, פרהקליני•

שיפור התוצאים של המחלה•

מניעה שניונית•

Characteristics of a good screening test

•Simple

•Rapid

•Inexpensive

•Safe

•Acceptable

הערכה של תכניות סריקה

מדדים אופרטיבים:מס' האנשים שנסרקו•אחוז אוכלוסיית היעד שנסרק ומס' הפעמים שבוצעה •

סריקההמצאות המחלה הפרה-קלינית•עלות כוללת•עלות פר מקרה מאובחן•עלויות עבור מקרים שבעבר היו בלתי ידועים•אחוז החיוביים בסריקה שאובחנו וטופלו••PPV

תוצאים:

הפחתת תמותה באוכלוסיה הנסרקת•

) case fatality rateהפחתת שיעור הקטלניות (•בקרב הנסרקים

עליה בשיעור המקרים המאובחנים בשלב •מוקדם

הפחתת סיבוכים, השנויות, גרורות•

שפור איכות החיים בנסרקים•

הערכה של תכניות סריקה

Evaluation of screening programs

• Evaluation is subject to several sources of bias

Selection bias:• Individuals who are motivated enough to

participate in screening programs may have a different probability of disease than individuals who refuse participation (volunteers, people at risk…)

Lead time biasa perception of longer survival among screen detected

cases simply because the disease was detected earlier in its natural course

Length biasPreclinical

stageClinical stage

Length biasdetection of slower growing tumors that have an inherently

better prognosis than rapidly growing tumors that are usually detected following

clinical manifestations

Length bias

Length-time bias suggests that annual screening is more likely to detect slow-growing tumors, while fast-growing and potentially lethal tumors are less likely to be detected.

Overdiagnosis Bias

Evaluation of screening programs

• Outcome– Mortality:

• Cause specific mortality• All cause

– Survival– Morbidity– Quality of Life

lead time

&

length bias

שתי גישות לסריקה

אוכלוסייתית:Population

based approach

סיכון גבוה:High-riskapproach

Population based approach (mass screening)

• Screening test applied to the entire population, regardless of any a priory information on individual risk

• Test must be:– Inexpensive– Noninvasive

• Can be considered public health approach

High-risk approach(selective/targeted screening)

• The screening test is applied to a high risk group

• More cost-effective• Screening test can be:

– More expensive– More invasive/inconvenient

• Requires a clinical action to identify the high-risk group to be targeted

Case finding (opportunistic screening)

• Utilization of screening tests for detection of conditions unrelated to the patient’s complaints.

• Example: – FOB for a patient who came to the physician

complaining of pharyngitis.– Screening for depression

Multiphasic screening

• Screening for more than one disease

• The use of >2 screening tests together among a large group of people

• Example: pre-employment screening

• Cost-effective

• Limitations: multiple comparisons

Screening programs considerations

• Frequency: higher frequency less interval cancers higher sensitivity

• Population: higher risk higher PPV

נזקים אפשריים של מבחני סריקה

עלות

תופעות לוואי וסיבוכים

– תיוגlabelling effect

מאחר והאנשים הם לכאורה בריאים

כל תוצא שלילי בעקבות סריקה הוא יאטרוגני ולחלוטין ניתן למניעה