Utilizing Biostatistics in Diagnosis,
Screening, and Prevention
Bindu Swaroop, MD
Hospitalist Program
Department of Medicine
University of California, Irvine
Learning Objectives
• Review important statistical concepts
• Understand how to apply these concepts to support high
value care decisions in both the inpatient and outpatient
setting
• Develop an individualized approach to screening,
diagnosis and treatment recommendations for your
patients
Essential Biostatistical Concepts
• Sensitivity and Specificity
Disease
Present
• Pretest and Posttest
probability
Disease
Absent
• Positive/Negative
Predictive Values
Test A
Positive
B
• Likelihood Ratios
Test C
Negative
D
• Number Needed to
Treat/Harm
Role of Diagnostic Tests
• To reduce uncertainty regarding a specific patient’s diagnosis
• Generally most appropriate for patients you feel have an
intermediate pre-test probability of a disease
• Test characteristics (i.e. likelihood ratios) should be
considered before ordering a test to help determine whether a
given test would significantly alter your pre-test probability
(and thus affect management)
Ex. if you estimate a patient’s pretest probability to be 10%
but the LR of a diagnostic test is only 2, then a positive test
result will still only yield around a 25% posttest probability
Likelihood Ratios
Using likelihood ratios:
1.
Use the estimated pretest
probability of disease as an
anchor on the left side of the
graph
2. Draw a straight line through
the known likelihood ratio,
either (+) or (-)
3. Where this line intersects the
graph on the right represents
the posttest probability of
disease
Likelihood Ratios
Using likelihood ratios:
1.
Use the estimated pretest
probability of disease as an
anchor on the left side of the
graph
2. Draw a straight line through
the known likelihood ratio,
either (+) or (-)
3. Where this line intersects the
graph on the right represents
the posttest probability of
disease
General Rules for Interpreting Likelihood Ratios
A LR greater than 1 increases the probability that the target disease is present,
and a LR less than 1 decreases the probability that the target disease is present.
LR
Interpretation
10
Increases the pretest probability of disease by ~ 45%
5
Increases the pretest probability of disease by ~ 30%
2
Increases the pretest probability of disease by ~ 15%
1
No change in the likelihood of disease
0.5
Decreases the pretest probability of disease by ~ 15%
0.2
Decreases the pretest probability of disease by ~ 30%
0.1
Decreases the pretest probability of disease by ~ 45%
Common Diseases, Tests and Likelihood Ratios
Disease
Test/Result
Acute cholecystitis
Abdominal ultrasound
Acute pulmonary
embolism
Pulmonary CT angiography
Breast cancer
Mammogram
SLE
Antinuclear antibody
Likelihood Ratio
LR(+)= 23.8
LR(−)= 0.05
LR(+) = 29.1
LR(−) = 0.05
LR(+)= 8.7
LR(−)= 1.4
LR(+)= 4.5
LR(−)= 0.125
Scenario 1: Approach To Chest Pain
• A 32 y/o woman presents with a 2 day history of dull, aching,
left-sided chest pain. She is physically active and exercises
regularly. She first noted her symptoms after exercise. Her
pain has been fairly constant since onset, but does seem to
worsen with certain positional changes and improves with
acetaminophen. There is no exertional component. She is
worried because her father had a heart attack at age 55.
• Past medical history is unremarkable with no active medical
issues. She is a non-smoker and a lipid profile 2 years ago
showed: total cholesterol of 185, LDL of 122, and HDL of 42.
Physical examination shows a BP of 122/68 mm Hg and a
heart rate of 68/min. Her lungs are clear and the heart
examination is completely normal. Her chest pain is
reproducible to palpation across the left costosternal margin.
• A resting ECG is completely normal.
Scenario 1:
Focus on the diagnostic process:
▫ Estimating the pretest probability of disease in your
patient
 What is the pre test probability this patient has ischemic
heart disease?
▫ Evaluate how cardiac stress testing in your patient
would influence your pretest probability of disease
 Will you perform additional testing to evaluate for
ischemic heart disease in this patient?
▫ Assess whether you believe that cardiac stress testing
would be helpful in your patient
 Use likelihood ratios to assess how testing might
influence your pre-test probability of the disease
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
4
2
34
12
76
26
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
30-39
4
2
34
12
76
26
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
30-39
4
2
34
12
76
26
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
30-39
4
2
34
12
76
26
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Cardiac Stress Test Characteristics
Test
Sensitivity
Specificity
ECG Stress Test
68%
77%
Echocardiographic Stress Test
85%
77%
Nuclear Medicine Stress Test
88%
74%
Likelihood Ratios
LR(+) = 2.9
LR(-) = 0.42
LR(+) = 3.7
LR(-) = 0.19
LR(+) = 3.4
LR(-) = 0.16
Scenario 2: Approach to Chest Pain
• A 47 y/o man presents with a 10 day history of left-sided chest pain. He
describes his symptoms as a mild ache that is ‘deep’ and does not change
with position. It comes and goes, and does not appear to be related to
exertion. There is no associated nausea or diaphoresis. He cannot relate
the onset of his pain to any acute event or activity. He has not had to limit
his work as a construction worker because of his symptoms, and says that at
times he forgets about his symptoms when he is busy at work.
• Past medical history is significant for mild overweight (BMI 28) and
hypertension that is well controlled with a daily dose of lisinopril. He has a
15 pack-year smoking history but has not smoked since age 25. A lipid
profile 2 years ago showed: total cholesterol of 225, LDL of 142, and HDL of
38. Physical examination shows a blood pressure of 128/80 mm Hg and a
heart rate of 78/min. His lungs are clear and the heart examination is
normal. The remainder of his examination is unremarkable.
• A resting ECG shows mild nonspecific ST-T wave changes but is otherwise
normal.
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
4
2
34
12
76
26
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
4
2
34
12
76
26
40-49
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Clinical Assessment of Pretest Probability of Ischemic Coronary Artery Disease
Pretest Probability
Nonanginal Chest Paina
Atypical Chest Painb
Typical Chest Painc
Age (y)
Men
Women
Men
Women
Men
Women
30-39
4
2
34
12
76
26
40-49
40-49
13
3
51
22
87
55
50-59
20
7
65
31
93
73
60-69
27
14
72
51
94
86
History and Physical Examination Features and Ischemic Coronary Artery Disease
History
LR
Physical Exam
LR
Pain in chest or left arm
LR(+) = 2.7
Third heart sound on auscultation
LR(+) = 3.2
Radiation to left arm
LR(+) = 2.3
Hypotension
LR(+) = 3.1
Radiation to right shoulder
LR(+) = 2.9
Crackles on lung examination
LR(+) = 2.1
Radiation to both arms
LR(+) = 7.0
Chest pain reproducible to palpation
Chest pain is primary symptom
LR(+) = 2.0
History of myocardial infarction
LR(+) = 1.5-3.0
Nausea/vomiting
LR(+) = 1.9
Diaphoresis
LR(+) = 2.0
Nature of chest pain:
Pleuritic
LR(-) = 0.2
Sharp or stabbing
LR(-) = 0.3
Positional
LR(-) = 0.3
LR(-) = 0.2-0.4
Focus on the diagnostic process:
▫ Estimating the pretest probability of disease in
your patient
-moderate (51%)
▫ Evaluate how cardiac stress testing in your patient
would influence your pretest probability of disease
-LR for treadmill stress test = 2.9
▫ Assess whether you believe that cardiac stress
testing would be helpful in your patient
-increase post test probability by ?
Scenario 3: Approach to Chest Pain
• A 68 y/o man presents with a 5 day history of left-sided chest pressure. He has a
history of coronary artery disease with stent placement in the RCA and an LAD
diagonal artery 3 years ago. He has had no cardiac symptoms since that time. His
current symptoms are similar to his prior chest pain symptoms. His chest pain is
exertional and responds to sublingual nitroglycerin.
• Past medical history is significant for hypertension, diabetes mellitus type 2,
hyperlipidemia, and sleep apnea, which is treated with nocturnal CPAP. Medications
include metformin, lisinopril, atorvastatin, isosorbide mononitrate, aspirin,
clopidogrel, and as-needed sublingual nitroglycerin. He is a non-smoker and a lipid
profile 6 months ago (on treatment): total cholesterol of 120, LDL of 65, and HDL of
32.
• Physical examination shows a BP of 122/82 mm Hg and heart rate of 72/min. BMI is
26. The lungs are clear and his heart examination shows a regular rate with normal
heart sounds and a 2/6 systolic murmur at the right upper sterna border. There is no
lower extremity edema, and the remainder of his examination is unremarkable.
• A resting ECG show normal sinus rhythm, with small Q waves in leads II, III and
aVF. There are no acute or ischemic changes.
Focus on the diagnostic process:
▫ Estimate the pretest probability of disease in your patient
Pretest Probability
Nonanginal Chest Paina
Men
Women
Age (y)
30-39
40-49
50-59
60-69
4
13
20
27
Atypical Chest Painb
Men
Women
2
3
7
14
34
51
65
72
12
22
31
51
Typical Chest Painc
Men
Women
76
87
93
94
26
55
73
86
▫ Evaluate how cardiac stress testing in your patient would influence your
pretest probability of disease
Test
ECG Stress Test
Sensitivity
68%
Specificity
77%
Echocardiographic
Stress Test
85%
77%
Nuclear Medicine
Stress Test
88%
74%
Likelihood Ratios
LR(+) = 2.9
LR(-) = 0.42
LR(+) = 3.7
LR(-) = 0.19
LR(+) = 3.4
LR(-) = 0.16
LR
Interpretation
10
Increases the pretest probability of disease by ~ 45%
5
Increases the pretest probability of disease by ~ 30%
2
Increases the pretest probability of disease by ~ 15%
1
No change in the likelihood of disease
0.5
Decreases the pretest probability of disease by ~ 15%
0.2
Decreases the pretest probability of disease by ~ 30%
0.1
Decreases the pretest probability of disease by ~ 45%
▫ Assess whether you believe that cardiac stress
testing would be helpful in your patient
Preventive Practice:
The Periodic Health Examination
• A 57-year-old woman presents for her
periodic health examination. She has not
been seen by a doctor for
ten years
• She has no past medical history except for a
hysterectomy for fibroids 10 years ago. She
takes no medications
• She is a retired teacher, lives alone, smokes
1 pack per day (38 pack years), does not use
alcohol or illicit drugs, and has not been
sexually active since her husband died 8 yrs
ago
• She has no family history of cancer,
vascular disease, or osteoporosis
• Her BP 135/83 and her BMI is 24, the
remainder of her exam is unremarkable
What Should be Included in her Preventive Care?
• Rank the top five preventive
services you might offer this
patient. Use the categories below
to help you.
▫ Immunizations
▫ Screening
▫ Behavioral counseling to
motivate lifestyle changes
▫ Chemoprevention
Preventive Care Menu
•
•
•
•
•
•
•
•
•
•
•
Influenza vaccine
Pneumococcal vaccine
Td/TDAP
Zoster vaccine
Smoking cessation
Weight loss
Exercise
Alcohol misuse
Aspirin
Statin therapy
Hepatitis C screening
•
•
•
•
•
•
•
•
•
•
•
Calcium/Vitamin D
Tamoxifen
Mammogram
Colonoscopy
Pap smear
HIV screening
Lung cancer screening (LDCT)
DEXA scan
HbA1C
Fasting lipid panel
Domestic violence screening
Role of Screening Tests
• To detect asymptomatic and early stage disease
• Should be highly sensitive and highly specific
to pick up most cases of true disease and avoid false
positives
• Targeted toward populations with a higher disease
prevalence (high positive predictive value)
• Should be relatively safe and cost-effective
• Should screen for diseases in which early
identification and treatment have been
demonstrated to improve clinical outcomes
Cost-effectiveness
“Cost-saving”
Reduces cost,
Improves Health
1
Costs money,
Improves Health
Costs money,
Worsens Health
• Measures that cost money but improve health can be further categorized
by their cost, often measured in dollars per QALY (quality-adjusted lifeyear)
• QALYs incorporate an estimate of the quantity of life gained by the
intervention, coupled with a more subjective assessment of the quality of
that life affected by the intervention
• Historically, payers have considered any intervention that has a costeffectiveness ratio of <$100K per QALY as acceptable
Cohen J, Neumann P, Weinstein M NEJM 2008:358;72
Examples of relative cost-effectiveness of different preventive measures.
• Colonoscopy for average risk patients costs $1000-3000 but provides a 20-30%
absolute mortality reduction (USPSTF grade A)
•
Mammography for average risk women ages 40-49 prevents only one death for
every 1000 women screened annually for 10 yrs (USPSTF grade B)
Common Harms Associated with Screening
False positive results
• Can lead to incorrect
labeling, inconvenience,
expense, and physical harm
in follow-up tests
“Overdiagnosis3” and
“Pseudodisease”
(Length-time bias)
USPSTF Recommendation Grades, Electronic
Preventive Services Selector (ePSS), and Vaccine
Scheduler
• USPSTF provides a tool for clinicians (ePSS) to
search for graded recommendations.
epss.ahrq.gov/PDA/index.jsp
• Vaccine recommendations are available in the
second tool.
www.cdc.gov/vaccines/schedules/Schedulers/adultscheduler.html
• The ACP also offers a downloadable Immunization
Advisor.
immunization.acponline.org/app/
USPSTF Recommendation Grades
Back to the Case:
• A 57-year-old woman presents for her
periodic health examination. She has not
been seen by a doctor for
ten years
• She has no past medical history except for a
hysterectomy for fibroids 10 years ago. She
takes no medications
• She is a retired teacher, lives alone, smokes
1 pack per day (38 pack years), does not use
alcohol or illicit drugs, and has not been
sexually active since her husband died 8 yrs
ago
• She has no family history of cancer,
vascular disease, or osteoporosis
• Her BP 135/83 and her BMI is 24, the
remainder of her exam is unremarkable
Back to the Case:
What 5 preventive services should
have been offered?
1. Aspirin for chemoprevention of
CVA – grade A
2. Colorectal cancer screening –
grade A
3. Lipid screening- grade A
4. Tobacco use counseling and
intervention – grade A
5. Influenza/pneumococcal
vaccine
Balancing Benefits and Harms
4
• Daily ASA use results in a 17% absolute risk reduction in ischemic
CVA for women and 32% absolute risk reduction for MI in men
• Major risk of daily ASA use is serious upper GI bleed
• Both the risk of major GI bleed (net harm) and the risk of ischemic
CVA (net benefit) increase with age
• Using data from large randomized controlled trials, USPSTF has
provided tables that estimate the absolute # of strokes and MI
prevented per 1000 women and men, respectively, stratified by
baseline stroke risk and age
• Baseline 10-yr CVA risk can be calculated using:
www.westernstroke.org/PersonalStrokeRisk1.xls
= 3.5% for our patient
Balancing benefits and harms
4
Balancing benefits and harms
4
ASA for the Prevention of Cardiovascular Disease:
U.S. Preventive Services Task Force Statement
What about for this patient?
• Mr. T is a 50 y/o male who comes to your office for routine followup
• He has heard that taking an aspirin may decrease his risk of a heart
attack and is wondering whether he should start taking daily aspirin
• Past medical history
▫
▫
▫
▫
▫
No family history of CAD
No personal history of CAD or gastrointestinal issues
His only medical history of HTN, well controlled with medication
His recent lipid profile shows total cholesterol of 160, HDL 50
PE in office with normal cardiac and general exam, BP 110/74
• How would you counsel him? What is the data?
• Use Framingham risk assessment calculator (10 year MI risk) at
hp2010.nhlbihin.net/atpiii/calculator.asp = 2%
Balancing benefits and harms
4
Summary
• Diagnostic tests should only be used if the result is
likely to significantly affect your certainty of a
disease (posttest probability)
• Preventive healthcare must be individualized with
the help of expert recommendations (USPSTF) to
offer patients interventions that are most likely to
positively impact their long-term healthcare goals
• Recommendations are not prescriptive, but rather
the beginning of an open dialogue with patients to
create a prioritized plan of preventive health
maintenance
References
1. Owens D, et al. High-value, cost-conscious health care: concepts for
clinicians to evaluate the benefits harms and costs of medical
interventions. Ann Intern Med. 2011; 154: 174-80
2. Cohen JT, et al. Does preventive care save money? Health
economics and the presidential candidates. N Engl J Med. 2008;
358:661-3.
3. Moynihan R, et al. Preventing overdiagnosis: how to stop harming
the healthy. BMJ. 2012; 344: e3502.
4. U.S. Preventive Services Task Force; Aspirin for the Prevention of
Cardiovascular Disease: U.S. Preventive Services Task Force
Recommendation Statement. Annals of Internal Medicine. 2009
Mar;150(6):396-404.