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Study Designs-Review Epidemiology 200A Dr. Jørn Olsen November 24, 2009 Fall 2009 1 Causation 1st Axiom: Diseases exist as a function of preceding causes causes exist causes (some) have a social or environmental history 2nd Axiom: Diseases are distributed as a function of susceptibility and exposures Host Exposure Environment Diseases follow sufficient causal fields 2 Causation 3rd Axiom: The manifestation of diseases is a function of treatment and natural defense mechanism. 4th Axiom: Diseases are not distributed at random. They are not unavoidable events. Some causes are man made. Therefore, some diseases are preventable. 3 Hume 1711-1776: We may define a cause to be an object followed by another and where all the objects similar to the first are followed by objects similar to the second. E D 4 Not many examples of E D associations in medicine. Causes in the ”strong-Hume” sense could be seen as necessary and sufficient causes A necessary cause E D several examples in medicine, but they are usually man-made tuberculosis post-partum depression AIDS, etc. A sufficient cause E D 5 Sexual debut is a risk indicator, maybe a risk factor or a cause (sexual activity is a necessary cause). E D 6 Causes act conditionally upon other causes and in combination they become a sufficient causal field. Each component cause is only sufficient given the other component causes exist. I A II B A III D C 70% B E F 20 % 10% Causes are only necessary for a subdomain of diseases (I, II or III) and they are only sufficient given the other causes are in place. The strength of a given association depends upon the 7 prevalence of the other component causes. DAG A air p B sex C bronchial response treatment E arc asthma D A A-C-D directed (causal) B adjacent > nodes E-C-D not directed Ancestor – descendant Acyclic if no directed path forms a closed loop 8 Measures of disease occurrence, measure of associations 9 Breast cancer screening trial 5year follow-up Screening N Obs. Time Death Yes 25,000 118,000 180 Yes 25,000 117,500 210 CI+, R+ 180/25,000 = 0.0072 CI-, R- 210/25,000 = 0.0084 IR+ 180/118,000 = 0.00153 IR- 210/117,500 = 0.00179 10 If disease is rare… R~ IR ~ disease-odds= (180/25,000) ~ (180/118,000) x 5 ~ (180/25,000) / (24820/25,000) 0.0072 ~ = 0.0076 ~ 0.0073 11 From incidence rates to incidence proportions Kaplan-Meir or exponential formula: ∑IR Δt k k k Conditions: 1-e 1) Closed population 2) No competing risks 3) Stable IR over Δt and IR is small 12 Associations RR = R+ / R- = 0.857 IRR = IR+ / IR- = 0.853 OR = Disease odds + / Disease odds - = 0.857 13 Attributable fractions Screening a preventive measure (for mortality). Treat lack of screening as ‘a causal exposure’. 210 die in the non-screened group. Had they had the same risk as the screened we would expect (180/25,000) x 25,000 = 180 deaths 30 deaths prevented out of 210 = 30/210 x 100 = 14% 14 Population or ( R- - R+) / R- = 1-RR (0.0084-0.0072) /0.0084 = 1-0.857 =0.14 Preventive fraction-Vaccine efficiency in infectious disease epidemiology 15 210+180 died in the population. 30 could have been prevented = 30/390 = 7.7% Formal procedure R- x N- - R+ N - R- x N- + R + x N+ 16 17 18 Prevalence and incidence Ix D = P/(N – P) in steady state population with no migration. I(N-P)Δt I (N-P) Δt = (1/D) P Δt I (N-P) = 1/D P I1PΔt or (1/D)PΔt I1 = incidence rate of leaving the prevalence pool I x D = P/(N-P) P/(N-P) prevalence odds; if P is small I x D ≈ P/N 19 Is the obesity epidemic leading to an epidemic of diabetes? The prevalence of diabetes is increasing but ? 20 21 22 Randomized Controlled Trial (RCT) Experimental studies: The researcher manipulates the exposure in order to study the effect of the exposure. The unit of observation is often individuals, but can be regions. Requires longitudinal data collection. Relies upon primary data or a combination of primary and secondary data. Is well suited to estimate the expected therapeutic efficacy in quantitative terms under ideal circumstances (efficacy). Does not usually provide evidence of unexpected effects (or side effects). Does not provide evidence of effects in routine circumstances (effectiveness). 23 Three key elements in a classic RCT Randomization: comparability of populations Placebo: comparability of circumstances Blinding: comparability of information 24 Basic structure of the RCT Set up a specific hypothesis Select a sampling frame among suitable patients Define inclusion/exclusion criteria Obtain informed consent Randomize Follow compliance Measure outcome Analyse according to intention to treat or according to protocol 25 Sequence Candidate patients Define source population / study base incl./excl. Criteria Informed consent randomize Compliance Loss to follow-up Effect Analyse: Intention to treat or According to protocol 26 Reporting from the trial should at least provide the information requested by the CONSORT group (Lancet 2001; 357: 1191-94). CONSORT: Consolidated Standards of Reporting Trials www.consort-statement.org 22-item checklist Detailed explanation of CONSORT in Altman et al. Annals of Internal Medicine 2001; 134: 663-694. 27 Screening for colorectal cancer Kronborg et al. Lancet 1996; 348: 1467-71. Figure 1: Study profile 28 Screening for colorectal cancer Kronborg et al. Lancet 1996; 348: 1467-71. Table 2. Compliance during repeated screening Screening round Number of people invited for screening Number of people screened 1 2 3 4 5 30,762 20,113 18,236 16,746 15,279 20,672 (67%) 18,781 (93%) 17,279 (94%) 15,845 (94%) 14,203 (92%) 29 Screening for colorectal cancer Kronborg et al. Lancet 1996; 348: 1467-71. 30 Classification of designs Unit of observation = individual or clusters of individual macroepidemiology / microepidemiology Allocation of exposure = experimental / non-experimental Longitudinal recording = survey / case-control or follow-up Selection of exposure or outcome = follow-up / case-control Source population = case-control; primary, secondary Data = primary / secondary Data collection = prospectively / retrospectively 31 31 Source: Kunzli et al. The Semi-individual Study in Air Pollution Epidemiology; A Valid Design as Compared to Ecologic 32 Studies. EHP 1997, 105 (10).