Clinical Epidemiology – the basics. What do the terms relative risk and absolute risk mean? What...
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Transcript of Clinical Epidemiology – the basics. What do the terms relative risk and absolute risk mean? What...
Clinical Epidemiology – the basics
• What do the terms relative risk and absolute risk mean? What are the advantages and disadvantages of each?
• A new screening test is described as having a sensitivity of 78%, a specificity of 89%,a positive likelihood ratio of 13 and a negative likelihood ratio of 0.05. Explain these terms.
A 2 minute exercise
• What do you know about this topic? Could you explain what you know to others?
• What bits would you like clarifying? (Hint – do you understand RR, OR, CIs etc)
EVIDENCE BASED MEDICINE
EBM is an approach to practicing medicine in which the clinician is aware of the evidence in support of his / her clinical practice, and the strength of that evidence.
EVIDENCE BASED HEALTHCARE
Evidence based health care promotes the collection, interpretation, and integration of valid, important and applicable patient-reported, clinician-observed and research derived evidence. The best available evidence, moderated by patient circumstances and preferences, is applied to improve the quality of clinical judgements and facilitate effective healthcare.
EFFECTIVE SAFE
COST PATIENTFACTORS
QUALITYOF CARE
SYSTEMATICAPPLICATIONOF THERAPY
100%0%
LEVELS OF EVIDENCE
• LARGE WELL DESIGNED RCT
• META ANALYSIS OF SMALLER RCTs
• CASE CONTROL AND COHORT STUDIES
• (CASE REPORTS AND CASE SERIES)
• CONSENSUS FROM EXPERT PANELS
• I THINK
Why don’t we always use an RCT then?
• Ethics
• Cost
• Feasibility
• Practicality
Why read journals?
• Need to make the best possible decisions for patients
• Need to make the best possible decisions for healthcare
• Need to feel confident about being “on top of the job”
• Need to feel knowledgeable themselves and credible with peers
WHY THE MOVE TO EBM?
• RANDOMISED CONTROLLED TRIALS PRE-1960 WERE ODDITIES
• REVIEWS AND META-ANALYSES AVAILABLE AS ACCESSIBLE DIGESTS OF EVIDENCE
• ACCESS TO EVIDENCE VIA I.T.
• METHODOLOGICAL ADVANCEMENTS E.G. NUMBERS NEEDED TO TREAT
EBM IS ABOUT ...
• CLINICAL EXPERIENCE, DIAGNOSTIC SKILLS AND CLINICAL INSTINCT ARE A NECESSARY PART OF A COMPENTENT PHYSICIAN.
• HOWEVER, CLINICAL PRACTICE BASED SOLELY UPON CLINICAL EXPERIENCE “BECOMES TOMORROW’S BAD JOKE”.
• “RATIONAL” TREATMENT BASED SOLELY UPON BASIC PATHOLOGICAL PRINCIPLES MAY IN FACT BE INCORRECT, LEADING TO INACCURATE TREATMENT.
• UNDERSTANDING CERTAIN RULES OF EVIDENCE IS NECESSARY TO CORRECTLY INTERPRET LITERATURE ON CAUSATION, PROGNOSIS, DIAGNOSTIC TESTS AND TREATMENT STRATEGY.
20,000 biomedical journals in print. So why isn’t all practice based on scientific evidence?
• Not RELEVANT– Upstream to clinical decisions being made, e.g. animal or in vitro
studies
– Study populations and / or settings do not reflect question type, practice population and settings.
• Not RELIABLE– Poor study design
– Bias and confounding
– Measurement validity
– Insufficient power
BIAS
• Selection bias
• Observer bias
• Participant bias
• Withdrawal or drop out bias
• Recall bias
• Measurement bias
• Publication bias
CONFOUNDING
COFFEE DRINKING LUNG CANCER
SMOKING
STUDY
CONFOUNDING VARIABLE
Power
The ability of the study to detect an effect if in truth there is an effect.
An RCT may be underpowered if:-
• The duration is too short (too few events)
• It includes too few people (too few events)
• The wrong outcome was used (too few events)
• Expecting a higher level of statistical proof than is realistic for the condition and the intervention being tested
EBM SKILLS - STATISTICS
• CHANCE - p = 1 in 20 (0.05).
• > 1 in 20 (0.051) = not significant
• < 1 in 20 (0.049) = statistically significant
• CONFIDENCE INTERVALS
• what is the range of values between which we could be 95% certain that this result would lie if this intervention was applied to the general population
TYPES OF STUDY - HYPOTHESIS FORMING
• CASE REPORTS / CASE SERIES
• CROSS SECTIONAL / PREVALENCE STUDIES measure personal factors & disease states – a snapshot
• CORRELATIONAL / ECOLOGICAL / GEOGRAPHIC STUDIES. prevalence &/or incidence measurement in one population c/w another pop.
TYPES OF STUDY - HYPOTHESIS TESTING
CASE CONTROL STUDIES
Controls
Population
CasesYes
No
Yes
No
Exposure to Risk Factor
TIME
STUDY
CASE CONTROL EXAMPLE -SMOKING & LUNG CANCER
DISEASE
Cases Controls
EXPOSURE Yes a b
EXPOSURE No c d
Odds Ratio = ad/bc
(1 = no association, > 1 = possible association, < 1 = protective effect)
DISEASE
Cases Controls
(lung cancer)
EXPOSURE Yes 56 230
(smoking) No 7 246
The odds ratio would therefore be 56 x 246 = 13776 = 8.6.
7 x 230 1610
TYPES OF STUDY - HYPOTHESIS TESTING
COHORT STUDIES
Population
Sample
Yes
No
Yes
No
Time
Exposed
Not exposed
COHORT STUDIES
OUTCOME
Yes No
Exposed a b
Not exposed c d
Relative risk "How many times are exposed persons more likely to
develop the disease, relative to non-exposed persons?" i.e. the incidence in the exposed divided by the incidence in the non-exposed.
This is expressed as a divided by c .
a+b c+d
COHORT STUDY EXAMPLE
Deep vein thromboses (DVT) in oral contraceptive users. (Hypothetical results).
OUTCOME (DVT)
Yes No
Exposed ( on oral contraceptive ) 41 9998
Not exposed (not on o.c.) 7 10009
These results would give a relative risk of 6 - significantly large enough numbers to indicate the possibility of a real association between exposure
and outcome. However, NB biases.
RANDOMISED CONTROLLED TRIALS
Population Sample Time
Improved
Not improved
Not improved
Improved
Experimental intervention
Comparisonintervention
RANDOMISED CONTROLLED TRIALS
OUTCOME
Yes No
Comparison intervention a b
Experimental intervention c d
Absolute risk reduction: “What is the size of this effect in the population”
Control event rate - experimental event rate
a/a+b - c/c+d
Relative risk reduction: “ How many fewer patients will get the outcome measured if they get active treatment versus comparison intervention”
a /a+b - c/c+d
a/a+b
ARR and RRRA quick test
• In a study lasting 12 months, the death rate on placebo was 10% and the death rate on Marvelicoxib was 5%.
• What is the ARR?
• What is the RRR?
ARR and RRR in more detail4S STUDY
• STABLE ANGINA OR MYOCARDIAL INFARCTION MORE THAN 6 MONTHS PREVIOUSLY
• SERUM CHOLESTEROL > 6.2mmol/l
• EXCLUDED PATIENTS WITH ARYHTHMIAS AND HEART FAILURE
• ALL PATIENTS GIVEN 8 WEEKS OF DIETARY THERAPY
• IF CHOLESTEROL STILL RAISED (>5.5) RANDOMISED TO RECEIVE SIMVASTATIN (20mg > 40mg) OR PLACEBO
• OUTCOME DEATH OR MYOCARDIAL INFARCTION (LENGTH OF TREATMENT 5.4 YEARS ) WERE THE OUTCOMES
RCT EXAMPLE - 4S STUDY
OUTCOME (death)
Yes No
Comparison intervention (placebo) 256 1967 2223
Experimental intervention (simvastatin) 182 2039 2221
The ARR is (256/2223) - (182/2221) = 0.115 - 0.082 = 0.033.
The RRR is 0.033/0.115 = 0.29 or expressed as a percentage 29%.
1/ARR = NUMBER NEEDED TO TREAT.
1/0.033 = 30.
i.e. if we treat 30 patients with IHD with simvastatin as per 4S study, in 5.4 years we will have prevented 1 death.
Another way of calculating NNTs
OUTCOME (death)
Yes No
Comparison intervention (placebo) 256 1967 2223
Experimental intervention (simvastatin) 182 2039 2221
Prevalence of event in control group = 256/2223x100=11.5%
RRR = 29%
Now that’s magic!
NNT EXAMPLES
Intervention Outcome NNT
Streptokinase + aspririn v.placebo (ISIS 2)
prevent 1 deathat 5 weeks
20
tPA v. streptokinase(GUSTO trial)
save 1 life withtPA usage
100
Simvastatin v. placebo in IHD(4S study)
prevent 1event in 5y
15
Treating hypertension in the over-60s
prevent 1 eventin 5y
18
Aspirin v. placebo in healthyadults
prevent MI ordeath in 1 year
500
Why are RCTs the “gold standard”Breast cancer mortality in studies of screening with mammography; women
aged 50 and over (55 in Malmo study, 45 in UK)
Relative risk
0.1 0.2 0.5 1.0 2.0
Reduced RR Increased RR
Randomised Trials
Geographical study
Case control studies
HIP
Two County
Malmo
Edinburgh
Stockholm
UK
BCDDP
Nijmegen
Utrecht
Florence
Egger M et al. Meta-analysis Spurious precision? Meta-analysis of observational studies BMJ 1998;316:140-144
Odds ratios or relative risks?Macfarlane J et al. BMJ 2002; 13: 105-9
Patients who took antibiotics
Patients who did not take
antibiotics
TOTAL
Patients who were given a leaflet
49 55 104
Patients not given a leaflet
63 38 101
TOTAL 112 93 205
Patients who took antibiotics
Patients who did not take
antibiotics
TOTAL
Patients who were given a leaflet
49 55 104
Patients not given a leaflet
63 38 101
TOTAL 112 93 205
Relative risk: (49/104) / (63/101) = 0.76.i.e the relative risk of patients taking an antibiotic if they were given a leaflet is reduced by 24%. Also calledrisk ratio.
Patients who took antibiotics
Patients who did not take
antibiotics
TOTAL
Patients who were given a leaflet
49 55 104
Patients not given a leaflet
63 38 101
TOTAL 112 93 205
Odds ratio: (49/55) / (63/38) = 0.54.There was a 46% reduction in the ratio of those taking antibiotics who had a leaflet compared with the ratio of those taking antibiotics who did not have a leaflet.
Patients who took antibiotics
Patients who did not take
antibiotics
TOTAL
Patients who were given a leaflet
49 55 104
Patients not given a leaflet
63 38 101
TOTAL 112 93 205
Absolute risk reduction: (49/104) – (63/101) = 0.15.Also known as the risk difference. i.e. the difference in the riskof taking antibiotics depending on whether a leaflet was usedor not.
Patients who took antibiotics
Patients who did not take
antibiotics
TOTAL
Patients who were given a leaflet
49 55 104
Patients not given a leaflet
63 38 101
TOTAL 112 93 205
NNT: 1 / 0.15 = 7. i.e. 7 people need to be given a leafletIn order for 1 additional person not to take antibiotics
Jüni P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior
to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287-1288
Screening and Diagnostic Tests
SCREENING - WILSON & JUNGEN (WHO, 1968)
• IS THE DISORDER COMMON / IMPORTANT
• ARE THERE TREATMENTS FOR THE DISORDER
• IS THERE A KNOWN NATURAL HISTORY & “WINDOW OF OPPORTUNITY” WHERE SCREENING CAN DETECT DISEASE EARLY WITH IMPROVED CHANCE OF CURE
• IS THE TEST ACCEPTABLE TO PATIENTS
• SENSITIVE AND SPECIFIC
• GENERALISABLE
• CHEAP / COST EFFECTIVE
• APPLY TO GROUP AT HIGH RISK
Tests ain’t what they used to beJoseph Heller Catch 22 1962
“Gus and Wes had succeeded in elevating medicine to an
exact science. All men reporting on sick call with
temperatures above 102 were rushed to hospital. All those
except Yossarian reporting on sick call with temperatures
below 102 had their gums and toes painted with gentian
violet solution and were given a laxative to throwaway in
the bushes. All those reporting on sick call with
temperatures of exactly 102 were asked to return in an
hour to have their temperatures taken again.”
0 10 20 30
NoDisease
A BDisease
Percentof population
No Disease
DiseaseNo Disease
VALUEArbitrary Units
Set cut off at A A lot of people who do not have the disease arelabeled as having it (false positives)
Set cut off at B A lot of people who do have the disease arelabeled as not having it (false negatives)
Disease
C
DISEASE
Present Absent
TEST
Positive
Negative
50
0
0
50
a b
c d
Measure the usefulness of the TEST by..
Positive
Negative
45
5
5
45
a b
c dTEST
Present Absent
DISEASE
Sensitivity Specificity
Sensitivity = a = 45 = 90% high sensy = a + c 50 few false negatives
Specificity = d = 45 = 90% high specy = b + d 50 few false positives
Test with a high specificity useful to rule in a diagnosis
e.g. before cancer chemotherapy
Test with high sensitivity useful to rule out a diagnosis
e.g. antenatal for syphilis
Sensitivity and specificity are properties of the test and are taken into account when deciding whether to test.
But……(and this is the hard bit so concentrate NOW)
When the test result is available the usefulness of the result depends on:-
1. How good (or bad) the test was at detecting true positives and true negatives
2. The pre-test probability of the person being tested actually having the disease for which they are being tested.
What is the pre-test probability of someone with dyspepsia being H pylori positive?
What is the pre-test probability of someone with dyspepsia being H pylori negative?
TEST
Positive
Negative
45 5
5 45
a bc d
Present Absent
DISEASE
Positive predictivevalue a = 45 = 90%a+b 50
Prevalence = 50%
Negative predictivevalue d = 45 = 90%c+d 50
Sens = 45/50i.e. 90%
Spec = 45/50i.e. 90%
The Impact of Prevalence on Predictive Value (Bayes Theorem)
DISEASE
Present Absent
9
1
9
81
a b
c d
TEST
POSITIVE
NEGATIVE
PPV = 9 = 50% 18
NPV = 81 = 99% 82
Sensitivity = 9 = 90% Specificity = 81 = 90% 10 90
Watch what happens when the prevalence drops to 10%…….
Likelihood ratios express how many more times (or less times) a test result is to be found in diseased people compared with non-diseased people.
TEST
Positive
Negative
Present Absent
a
c
b
d
DISEASE
LR +ve = a LR -ve = ca + c a + c
b db + d b + d
This change can be described arithmetically by likelihood ratios.
Likelihood ratios - EXAMPLE
TEST
POSITIVE
NEGATIVE
DISEASE
PRESENT ABSENT
9 9
1 81
a b
c d
LR +ve = 0.9 = 10 LR -ve = 0.1 = 0.120.09 0.81
New non-invasive tests for H. Pylori Gastritis. Comparison with tissue-based gold standard.
Douglas O, et al. Digestive Diseases and Sciences 1996; 41:740-8
Urea Breath Test
Sens. Spec.
LR +ve LR -ve
90 96 22 0.10
Serum Anti-bodies 74 89 7 0.30
Here comes another (different) magic nomogram!
+ve -vePrevalence PTP PTP
UBT 20% 85% 2%40% 95% 5%
Sab 20% 60% 5%40% 80% 12%
PTP - Post-test probabilityUBT - urea breath testSab - serum antibody test
+ve -vePrevalence PTP PTP
UBT 20% 85% 2%40% 95% 5%
Sab 20% 60% 5%40% 80% 12%
PTP - Post-test probabilityUBT - urea breath testSab - serum antibody test
H Pylori infection in a population with a 25% prevalenceMeReC Bulletin 2001; 12 (1): 1-4
646945475.586Near-patient serological tests
32597759091Laboratory serological tests
112998895.597.5Breath test (14C)
11199899696.5Breath test (13C)
False Negative results (%)
False positive results (%)
Negative predictive value (%)
Positive predictive value (%)
Specificity (%)
Sensitivity (%)
SUMMARY
EVIDENCE BASED MEDICINE
FORMULATE QUESTION
EFFICIENTLY TRACK DOWN BESTAVAILABLEEVIDENCE
CRITICALLY REVIEW THEVALIDITY AND USEFULNESSOF THE EVIDENCE
IMPLEMENT CHANGESIN CLINICAL PRACTICE
EVALUATE PERFORMANCE
“The evidence isn’t there” (whinge, moan) OR “I don’t have the time” (whine, complain)
• Clinical Evidence
• Cochrane
• DTB, MeReC Bulletin
• PRODIGY
• Evidence Based Medicine
LIMITATIONS
• STILL LOTS OF ROOM FOR DEBATE ABOUT THE EVIDENCE BASE
• EBM = WHAT IS BEST FOR AN INDIVIDUAL PATIENT (patient utility)
• EVIDENCE BASED PURCHASING = BEST USE OF HEALTH CARE RESOURCES FOR THE LOCAL POPULATION (cost utility). i.e. knowledge of local needs, priorities and constraints
• WHAT IF THESE CONFLICT? (Anybody want to mention beta interferon and MS?!)
EBM VISION FROM 1996
DOCTOR Consultation PATIENT
Critical Appraisal Skills
Systematic reviewsIndividual studies and reports
GUIDELINES
ELECTRONIC, PATIENT-SPECIFIC REMINDERS
Individual database searches
Disease
informationspecific
CONSULTATION SKILLSCONSULTATION SKILLS