Clinical epidemiology

I am not an expert but I will do my best!

If you know and I don’t - speak up! This is the basics - there is a major

new literature to become familiar with and new skills to learn.

www.bradfordvts.co.uk

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.

EVIDENCE BASED MEDICINE

FORMULATE QUESTION

EFFICIENTLY TRACK DOWN BESTAVAILABLEEVIDENCE

CRITICALLY REVIEW THEVALIDITY AND USEFULNESSOF THE EVIDENCE

IMPLEMENT CHANGESIN CLINICAL PRACTICE

EVALUATE PERFORMANCE

AN EXAMPLE OF EBM AND AN INDIVIDUAL PATIENT

THE PROBLEM New patient. 11 year old girl.

Generalised tonic clonic fits aged 5-8. On sodium valproate, no fits 3 years.

Parents disappointed with progress at school. Generally lethargic. “It’s the tablets - what would happen if we stopped them?”

SOLUTION 1

Do what the last consultant said.Advantage:

Consistency

Disadvantages:

Getting the notes

Do the letters say what to do long term?

Is that advice now out of date?

Was it correct at the time?

SOLUTION 2 Get a new consultant opinion

Advantages:Local secondary care contact made if needed in

the future

Advice will be current if the question is asked and answered

Disadvantages:Time till appointment.

Getting to hospital

Is the advice based on up to date knowledge or just clinical experience?

Resources

SOLUTION 3

CAN I FIND THE ANSWER MYSELF?

P EHRHARDT & WI FORSYTHE LEEDS GENERAL INFIRMARY DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY 31 (5) 633-

9; OCT 1989 From a total group of 640 children with grand mal seizures, 187 who

became seizure free for three consecutive years on monotherapy which was then discontinued have been followed for between 1 and 14 years. Relapse occured in 22 children (12%) and was related to age at presentation: only four of 89 children with primary grand mal seizures who had presented after the age of 3 years relapsed, compared with 12 of the 45 who had presented before their third birthday. Children who had had more seizures were at greater risk of relapse. EEGs were not useful in predicting prognosis, whether taken at presentation or before withdrawal of treatment.

BARRIERS TO IMPLIMENTING EBM FOR INDIVIDUAL PATIENTS

Cost Time It’s new What will patients think What will my colleagues think I don’t have the skills to assess the

quality of the evidence

WHY THE MOVE TO EBM?

RANDOMISED CONTROLLED TRIALS PRE-1960 WERE ODDITIES

REVIEWS AND META-ANALYSES ARE BECOMING AVAILABLE AS ACCESSIBLE DIGESTS OF EVIDENCE

ACCESS TO EVIDENCE VIA I.T. METHODOLOGICAL ADVANCEMENTS E.G.

NUMBERS NEEDED TO TREAT

THE ALTERNATIVE TO EBM

UNSYSTEMATIC CLINICAL OBSERVATIONS OVER TIME ARE A VALID WAY OF BUILDING AND MAINTAINING KNOWLEDGE ABOUT PROGNOSIS, THE VALUE OF TESTS, & THE EFFICACY OF TREATMENT

UNDERSTANDING BASIC MECHANISMS OF DISEASE AND PATHOPHYSIOLOGY ARE A SUFFICIENT GUIDE FOR CLINICAL PRACTICE

THOROUGH TRADITIONAL MEDICAL TRAINING PLUS COMMON SENSE IS SUFFICIENT TO EVALUATE NEW TESTS AND TREATMENTS

CONTENT EXPERTISE AND CLINICAL EXPERIENCE ARE SUFFICIENT FROM WHICH TO GENERATE CLINICAL GUIDELINES

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 RULESOF EVIDENCE IS NECESSARY TO CORRECTLY INTERPRET LITERATURE ON CAUSATION, PROGNOSIS, DIAGNOSTIC TESTS AND TREATMENT STRATEGY.

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

EBM SKILLS - A BASIC INTRODUCTION

CHANCE, BIAS, CONFOUNDING VARIABLES

COFFEE DRINKING LUNG CANCER

SMOKING

STUDY

CONFOUNDING VARIABLE

TYPES OF STUDY - HYPOTHESIS FORMING

CASE REPORTS / CASE SERIES CROSS SECTIONAL / PREVALENCE STUDIES

measure personal factors & disease states - hypothesis FORMING - cannot indicate cause & effect

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

Attributable risk (absolute risk or risk difference)

"What is the incidence of disease attributable to exposure"

Answer = a - c.

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 9996

Not exposed (not on o.c.) 7 10009

These results would give an attributable risk of 34 and a relative risk of 6 - significantly large enough numbers to indicate the possibility of a real

association between exposure and outcome. However, the possibility of biases very often arises.

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

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

Absolute risk reduction: “What is the size of this effect in the population”

a/a+b - c/c+d

RCT EXAMPLE - 4S 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.

NNT EXAMPLES

Intervention Outcome NNT

Streptokinase + asprirn 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

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

SCREENING

DISEASE

PRESENTABSENT

TEST POSITIVE A B

NEGATIVE C D

Sensitivity = a/a+c; Specificity = d/b+d;

positive predicitive value = a/a+b;

negative predicitve value = d/c+d.

Value of exercise ECG in coronary artery stenosis

DISEASE

PRESENT ABSENT

TEST POSITIVE 137 11

NEGATIVE 90 112

Sensitivity = a/a+c = 60%; Specificity = d/b+d = 91%;

positive predicitive value = a/a+b = 93%;

negative predicitve value = d/c+d = 55%.

Sensitivities and Specificities for different tests

Alcohol dependency or abuse(as defined by extensive investigations in

medical and orthopaedic in patients)

SENS SPEC

GGT 54% 76%

MCV 63% 64%

LFTs 37% 81%

“Yes” to 1 or > of CAGE ?s 85% 81%

“Yes” to 3 or > of CAGE ?s 51% 100%

MAKING SENSE OF THE EVIDENCE - ARE THESE RESULTS VALID -i.e. should I believe them?

Randomised (where appropriate)? Drop outs and withdrawals? Followup complete? Analysed in the groups to which

randomised?-

“Intention to treat”.

MAKING SENSE OF THE EVIDENCE- ARE THESE RESULTS USEFUL?-

i.e. should I be impressed by them, are they relevant to my patients (GENERALISABLE)

How large was the treatment effect?

How precise was the estimate of treatment effect

Were all important clinical outcomes considered?

Do benefits outweigh risks?

READING CRITICALLY

GENERAL– The aims of the study are not stated– The study is not original in concept– The study is not particularly useful or

relevant to general practice– There could be ethical objections to the

design or reporting of the study

READING CRITICALLY METHOD

– The design of the study is not consistent with the aims

– The sample is not representative of the whole population in question

– Controls are needed and not used– Controls used are not appropriate– Method(s) used for selecting cases / controls not

clearly described– Other method details (e.g. numbers, time periods,

statistical methods used) are not clear and consistent– Questionaires and proformas are not thoroughly

tested or are not relevant.

READING CRITICALLY RESULTS

– There is missing data. e.g. drop-out rates, non-responders– Other details e.g. numbers, percentages, p values are

inaccurate / unclear– Statistical methods would be useful but are not used– Statistical testing is used but is inappropriate– The tests of significance used do not meet the conditions

for the application of these tests– The sample size is so small that potentially clinically

significant findings do not achieve statistical significance– The sample size is so large that statistically significant

findings have little clinical significance

READING CRITICALLY

DISCUSSION– The study is not discussed critically– The results are not discussed in relation

to other important literature in the field– The discussions and conclusions

speculate too far beyond what has been shown in this study

THE COMMONEST ERRORS ARE:- ERRORS IN SAMPLE GROUPS OR

QUESTIONAIRE DESIGN FAILURE TO DESCRIBE THE METHOD

CLEARLY PROBLEMS WITH ALTERNATIVE RISK

FACTORS, EXCLUSIONS AND WITHDRAWLS

END POINTS AND DIAGNOSTIC DEFINITIONS UNCLEAR

POPULATION IS NOT TYPICAL OF MINE

GUIDELINES - SELECTING DISEASE OR CONDITION

HIGH MORBIDITY OR MORTALITY VARIATION FROM LOCAL OR NATIONAL PATTERN MAJOR SERVICE USER e.g.. stroke, arthritis, mental health CURRENT SERVICES OF QUESTIONABLE EFFECTIVENESS OR

EFFICIENCY PRIORITIES - LOCAL OR NATIONAL “NOISE” - CLINICAL

DEVELOPMENT OR RECOGNITION THAT IMPROVEMENT POSSIBLE

BE REALISTIC - e.g.. review D&Cs, not the whole of gynae services.

“The evidence isn’t there”

Bandolier Evidence Based Medicine DTB, MeReC CRD– Effective Healthcare Bulletins– Effectiveness Matters– Database of Abstracts of Reviews of

Effectiveness – Cochrane libraray

“GPs will never find the time to track the evidence down”

A lot has already been tracked down, critically appraised and packaged

A practice that collectively can find an hour a week can make huge strides

GPs don’t have to DO the work personally! - others (in the PHCT, at universities and at health authorities) can make a valid contribution

“GPs don’t have the skills and experience to critically appraise the

evidence and determine its applicability to their locality.”

A great deal of evidence has already been appraised

It’s not difficult! Critical appraisal skills have been shown

to work (in randomised controlled trials!) Who else is in a position to determine

applicability other than the local PHCT!

“The relevant evidence cannot be recalled during the consultation when

the answers are required”

COMPUTERS! Most consultations do not require

individual literature searching; for those that do a further appointment is no real hardship

Major areas of health gain can be handled with electronic reminders

EBM IN THE FUTURE

DOCTOR Consultation PATIENT

Critical Appraisal Skills

Systematic reviewsIndividual studies and reports

GUIDELINES

ELECTRONIC, PATIENT-SPECIFIC REMINDERS

Individual database searches

Disease

informationspecific

CONSULTATION SKILLSCONSULTATION SKILLS

LIMITATIONS

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?