אבחנה וסריקה diagnostic and screening tests ד"ר רונית קלדרון-מרגלית

Screening vs. Diagnosis screening negativepositive diagnosis No disease Have disease 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 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

Percentage distribution of serum cholesterol levels (mmol/L) in men aged 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

התבחין: תוקף ומהימנות Validity 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: רגישות - sensitivity – עד כמה התבחין רגיש לזהות את החולים סגוליות - specificity – עד כמה התבחין סגולי בזיהוי הבריאים עבור השימוש הקליני: ערך ניבוי חיובי – positive predictive value ערך ניבוי שלילי – negative predictive value

הערכת תוקף Disease AbsentPresent False positive True positive Abnormal Test True negative False negative Normal

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal Sensitivity = a/(a+b)

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal Specificity = d/(c+d)

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal Accuracy = (a+d)/(a+b+c+d)

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal Positive predictive value = the probability of an individual with an abnormal result to have the disease = a/(a+c)

Disease AbsentPresent False positive c True positive a Abnormal Test True negative d False negative b Normal Negative predictive value = the probability of an individual with a normal result to be free of disease = d/(b+d)

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions Sensitivity= TP rate =215/230=93%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions Specificity= TN rate =1822/2070= 88%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions Sensitivity= TP rate =215/230=93%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) The sensitivity, specificity and predictive values of the CK test in myocardial infarction among general hospital admissions Specificity= TN rate =114/130= 88%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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%

No MIMI Positive (>80IU)CK test results Negative (<80 IU) 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 Men, age 75 or greater Clinically suspicious prostatic nodule 50,

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

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; 341:461–7 Screening for Down’s syndrome

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91% A. 90% clinical probability Coronary Disease +- T PPV 98% Exercise NPV 20% ECG T

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91% cont. B. 5% Clinical probability +-T PPV 26% Exercise NPV 98% ECG T

Usefulness of exercise ECG in 3 patients: sensitivity 60%, specificity 91% cont. C. 50% Clinical probability +-T PPV 87% Exercise NPV 69% ECG T

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 symptomsdiagnosis 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 סריקה המצאות 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 הפחתת שיעור הקטלניות (case fatality rate) 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 bias a perception of longer survival among screen detected cases simply because the disease was detected earlier in its natural course

Length bias Preclinical stage Clinical stage

Length bias detection 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-risk approach

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  תיוג – labelling effect מאחר והאנשים הם לכאורה בריאים כל תוצא שלילי בעקבות סריקה הוא יאטרוגני ולחלוטין ניתן למניעה