Clinical epidemiology

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 EVALUATE PERFORMANCE IMPLEMENT CHANGES IN CLINICAL PRACTICE EFFICIENTLY TRACK DOWN BEST AVAILABLE EVIDENCE CRITICALLY REVIEW THE VALIDITY AND USEFULNESS OF THE EVIDENCE 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 Is that advice now out of date?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) 6339; 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 STUDY COFFEE DRINKING LUNG CANCER SM OKING CONFOUNDING VARIAB LE 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 Ex pos ure to Ris k Factor STUDY Y es Cas es No Population Y es Controls No TIM E CASE CONTROL EXAMPLE -SMOKING & LUNG CANCER DISEASE Cases Controls a b c d Yes EXPOSURE No Odds Ratio = ad/bc EXPOSURE (1 = no association, > 1 = possible association, < 1 = protective effect) DISEASE Cases Controls EXPOSURE (smoking) Yes No (lung cancer) 56 7 230 246 The odds ratio would therefore be 56 x 246 = 13776 = 8.6. 7 x 230 1610 TYPES OF STUDY - HYPOTHESIS TESTING  COHORT STUDIES Ex pos ed Popul ation Sam ple Tim e Y es No Y es Not ex pos ed No COHORT STUDIES OUTCOME Yes a c Exposed Not exposed No b 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 a+b divided by c c+d . COHORT STUDY EXAMPLE Deep vein thromboses (DVT) in oral contraceptive users. (Hypothetical results). OUTCOME (DVT) Yes Exposed ( on oral contraceptive ) 41 Not exposed (not on o.c.) 7 No 9996 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 Ex perimental interv ention Improv ed Not improv ed Population Sample Time Improv ed Comparis on interv ention Not improv ed 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 256 1967 182 2039 Comparison intervention (placebo) 2223 Experimental intervention (simvastatin) 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 Streptokinase + asprirn v. placebo (ISIS 2) Outcome prevent 1 death at 5 weeks save 1 life with tPA usage prevent 1 event in 5y prevent 1 event in 5y prevent MI or death in 1 year NNT 20 100 15 18 500 tPA v. streptokinase (GUSTO trial) Simvastatin v. placebo in IHD (4S study) Treating hypertension in the over-60s Aspirin v. placebo in healthy adults 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) Reduced RR R a n d o m is e d Tri a l s HIP Increas ed RR T wo Count y Malmo Edinburgh St ockholm G e o g ra p h i c a l s tu d y UK Ca s e c o n tr o l s tu d i e s BCDDP Nijmegen Ut recht Florence 0.1 0.2 Rel ati v e ri s k 0.5 1.0 2.0 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 PRESENT ABSENT B D TEST POSITIVE NEGATIVE A C 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 11 112 TEST POSITIVE NEGATIVE 137 90 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 54% 63% 37% 85% 51% SPEC 76% 64% 81% 81% 100% GGT MCV LFTs “Yes” to 1 or > of CAGE ?s “Yes” to 3 or > of CAGE ?s 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, nonresponders – 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 Critical Appraisal Skills Individual studies and reports Systematic reviews Individual database searches Disease specific information GUIDELINES ELECTRONIC, PATIENT-SPECIFIC REM INDERS DOCTOR Cons ultation PATIENT CONSULTATION SKILLS CONSULTATION 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?