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This document defines key concepts in epidemiology and study design. It discusses research questions, hypotheses, study factors, outcome factors, populations, sampling, bias, confounding, risk, prevalence, incidence, relative risk, statistical power, and study designs including cohort studies, case-control studies, and randomized controlled trials. It also defines internal and external validity and threats to validity.
This document defines key concepts in epidemiology and study design. It discusses research questions, hypotheses, study factors, outcome factors, populations, sampling, bias, confounding, risk, prevalence, incidence, relative risk, statistical power, and study designs including cohort studies, case-control studies, and randomized controlled trials. It also defines internal and external validity and threats to validity.
This document defines key concepts in epidemiology and study design. It discusses research questions, hypotheses, study factors, outcome factors, populations, sampling, bias, confounding, risk, prevalence, incidence, relative risk, statistical power, and study designs including cohort studies, case-control studies, and randomized controlled trials. It also defines internal and external validity and threats to validity.
Clinical Epidemiology and Biostatistics RESEARCH QUESTION
This is the essential question the study is set up to answer. Most studies are concerned with assessing one of four types of objectives: to assess the magnitude of a health problem or health factor; to assess the efficacy of an intervention; to asses the causal relation between one factor or set of factors and the disease or outcome of interest; or to asses the natural history of disease HYPOTHESIS
A proportion about the relationship between two or more factors or variables of interest. The purpose of the study is to collect data which will allow the researcher to test the hypothesis. In some studies the hypothesis may not be stated but it is implicit. (However, not all studies test hypotheses. Some times descriptive studies are called hypothesis generating). Hypotheses are often started in a null form, so as to allow them to be refuted. STUDY FACTOR
The exposure or variable of interest that is hypothesized to be related to the health problem, disease or outcome of interest. As the independent variable. For example, in a study of salt intake and its relationship to blood pressure, the study factor is salt intake. Must be quantifiable, but it may be assessed by a variety of means both direct and indirect, objective and subjective OUTCOME FACTOR
The event or occurrence that is supposed to have happened as a result of the influence of the study factor. The example: the outcome factor is blood pressure, it being seen to be influenced by the study factor, salt intake. The outcome factor is also know as the dependent variable May also be measured by a variety of methods direct and indirect, objective and subjective POPULATION The whole collection of units (individuals, cases, events) from which a sample may be drawn; and which must be defined geographically and temporally.
REFERENCE POPULATION This is an abstract concept of the people to whom the researcher wishes to refer results. Also known as the target population. SOURCE POPULATION
In setting up a study it is frequently impossible or impractical to include all of the reference population and the researcher will have to resort to a subset known as the source population. The population that is included in the study actually comes from and its specifications will be more limited than the reference population SAMPLING FRAME
To access the source population the researcher requires a sampling frame or study frame which will represent the source population. The simplest sampling frame would be complete listing of all the population. From this sampling frame a sample is collected which may consist of all or part of the frame. As not all of those identified in the sample will be available or willing to participate in a study, those that do will comprise the final study subjects. STUDY SAMPLE
This is the subject selected by random or non-random means from the sampling frame to represent the source population. In some studies it is possible to study the entire source population for the period of the study and there is no necessity to draw a sample SAMPLING
A process for selecting a study sample from the sampling frame when it is impractical to use the complete source population. The usual preferred method is random sampling whereby inclusion in the study sample is decided by chance. The objective of sampling is to select a non biased sample which can be studied. The hierarchy of sampling can be illustrated in the sample given below: Source Population- the broad group of people from whom the subjects will be obtained, i.e., school children in the Hunter Region. Sampling Frame the list of potential subjects from which a sample will be drawn, i.e., class lists of all Public Schools in the greater Newcastle area Reference Population the abstract concept of people to whom the results would apply-in these case- Australian school children Study Subjects Sample Sampling Frame Source Population Reference Population A researcher wants to study the prevalence of hearing defects in Australian school children.
Sampling Frame the list of potential subjects from whom which a sample will be drawn, i.e. class lists of all Public Schools in the greater Newcastle area. Sample- the subjects who are selected to take part in the study, e.g. a random selection of 25% of each class in each of the 8 schools which have been randomly selected from the 40 in the greater Newcastle area Sample Subjects- these provide the data, e.g. 90% of children had parental approval to take part in the study. BIAS
Any effect at any stage of investigation (or inference) tending to produce results that depart systematically (i.e., not randomly) from the truth. Many varieties of bias have been described including measurement bias, selection bias and confounding bias
CONFOUNDER
A factor that distorts the apparent magnitude of the effect of the study factor on the outcome factor. A confounder is it self a determinant of the outcome of interest, and is unequally distributed among the subjects that are exposed or not exposed to the study factor. For example, in a study of the influence of maternal nutrition on the birth weight of newborns (where it is hypothesised that women with a poor diet will have low birth weight infants), smoking is a confounding factor if women with poor dietary habits are also more likely to smoke (and it is known that smoking is of itself a risk factor for low birth weight infants) RISK Probability that an event will occur, e.g., that an individual will die or become ill within a stated period of time or age
ATTRIBUTABLE RISK The difference between the rate of disease in the exposed population and the rate in the non-exposed population. It is a measure of the amount of disease that might be reasonably attributed to the exposure in question.
RISK FACTOR An attribute or exposure that increases the probability occurrence of disease or a specified outcome. This defines risk factor as a determinant of the outcome, though risk factor can be used to denote association with a specified outcome that is not necessarily causal (i.e., a risk marker or risk indicator, (e.g., smoking and positive parental history are considered risk factors for coronary artery disease.
PREVALENCE The total number of all individuals who have the disease or factor or interest at a particular time or during a particular period ( the numerator) divided by the population at risk of having the disease at this time ( the denominator)
INCIDENCE
The number of new cases of a disease occurring in a defined population within a specified period of time. Usually expressed as the incidence rate which has the number of new cases of a disease in a defined period of time as the numerator and the number of persons in the stated population in which the cases occurred as the denominator. RELATIVE RISK
It is one measure of the strength of effect of an exposure on the likelihood of a particular outcome and is the ratio of risk of disease or death among those exposed to the study factor, to the risk of disease or death among those not exposed to the study factor. Note, that to calculate relative risk, it is necessary to use incidence figures for disease or death. As some study designs preclude this possibility, an approximation to relative risk, called the odds ratio is used instead. (STATISTICAL) POWER This is the probability that a study will detect a statistically significant difference when a difference really exists.
COHORT STUDY The study population is classified according to exposure to the study factor prior to the development of the outcome of interest. The incidence of the outcome is then ascertained in groups with different exposure status CASE CONTROL (OR CASE REFERENT) STUDY The study sample consists of a group with the outcome of interest (cases) and a sample of controls representative of the same source population from which the cases arose. The prevalence of exposure to the study factor in each group at a time prior to the development of the outcome in the cases is compared
RANDOMIZED CONTROLLED TRIAL An epidemiological experiment whereby the incidence of the study outcome(s) is compared in groups assigned by chance to different interventions and usually one group (the control group) who are not exposed. The aim of randomization is to achieve an equal or at least unbiased distribution of confounders, particularly unmeasured or potential confounders in exposed and non exposed groups STUDY VALIDITY The degree to which the inference drawn from a study, especially generalisations extending beyond the study sample, are warranted when account is taken of the study methods, the representativeness of the study sample, and the nature of the population from which it is drawn. Two varieties of study validity are distinguished (Last): 1. Internal Validity. The groups being compared (treated vs. non-treated, exposed vs. non-exposed or cases vs. controls) have been selected and measurements made in such a way that the results can be considered a good approximation to truth.
2. External Validity. The subjects in the study are selected and described in such a way that the results, given internal validity, can be applied or generalized outside of the study sample.
Threats to internal validity come from systematic error or bias. Threats to external validity come from the selection and sampling of subjects for a study . In order to see whether a study has external or generalizability it is important to have a clear idea of where the subjects have come from MEASUREMENT ISSUES
Epidemiology is very much about making measurements and about being critical of the measurements that are made by ourselves and other. There are two issues with all measurements which will be defined here. They are Validity and repeatability.
1. Measurement validity. An expression of the degree to which a measurement measures what it purports to measure, e.g., an autopsy has more validity than a biopsy or x-ray diagnosis
2. Repeatability. Critical to the validity of test is its repeatability, i.e., the degree of stability exhibited when the measurement is repeated under identical conditions. Most biological measurements show some variation when repeated. STUDY EFFICIENCY
This addresses the issues of the cost of obtaining information. the effects or end-results achieved in relation to the effort expended in terms of money, resources, and time (Last). Case control studies for example, are considered to be more efficient than longitudinal studies at obtaining information about the effect of an exposure or an outcome. This is because less effort needs to go into acquiring data by comparing diseased and non-diseased people for their exposure versus comparing exposed and non-exposed people for whether they develop an outcome Critical Appraisal using Epidemiology a Basic Methods. Critical Appraisal ( Including Study Terminology). University of Newcastle; 1994. CRITICAL APPRAISAL WORKSHEET (CAW) A General approach to critical appraisal of scientific literature The worksheet is a matrix composed of nine rows of questions about the paper, and three columns in which you are:
firstly whether the information to answer the question is available in the paper;
secondly, whether they was a problem with the way in which it was handled and;
thirdly, whether the problem identified was sufficient to affect the validity of the study CRITICAL APPRAISAL WORKSHEET (CAW) (1991) (1) (2) (3) Can you find this information in the paper? Is the way this was done a problem? Does this problem threaten the validity of the study 1. What is the research question and/or hypothesis?
2. What is the study type?
3. What is the reference population? What are the sampling frame and sampling method? Is it concerned with the impact on an intervention, causality, or determining the magnitude of a health problem? Is the study type appropriate to the research question ?
Is the sampling frame appropriate for the reference population Is there selection bias?
If not, how useful are the results produced by this type of study? Do these threaten the external validity of the study CRITICAL APPRAISAL WORKSHEET (CAW) (1991)
(1) (2) (3) Can you find this information in the paper? Is the way this was done a problem? Does this problem threaten the validity of the study
4. What are the study factors and how are they measured?
5.What are the outcome factors and how are they measured?
Is there measurement error?
a. Are all relevant outcomes assessed? b.Is there measurement error?
Is measurement error an important source of bias?
a.How important are omitted outcomes? b.Is measurement error an important source of bias? CRITICAL APPRAISAL WORKSHEET (CAW) (1991)
(1) (2) (3) Can you find this information in the paper? Is the way this was done a problem? Does this problem threaten the validity of the study
6. Are these sources of bias relevant to the study? Selection bias, recall bias, ascertainment bias, confounding bias, non-random assignment, incomplete follow- up
Have steps been taken to avoid these biases?
Is the internal validity of the study threatened by bias? CRITICAL APPRAISAL WORKSHEET (CAW) (1991) (1) (2) (3) Can you find this information in the paper? Is the way this was done a problem? Does this problem threaten the validity of the study 7. Are sample size issues considered? Is the power of the study indicated?
8. Are statistical methods described?
Is the sample size sufficient to detect clinically/ socially meaningful differences
Are the proposed statistical methods appropriate for addressing the stated research question and/or hypothesis? Are the proposed statistical methods appropriate for the data?
Do the conclusions drawn follow logically from the results of the analyses? CRITICAL APPRAISAL WORKSHEET (CAW) (1991) (1) (2) (3) Can you find this information in the paper? Is the way this was done a problem? Does this problem threaten the validity of the study 9. What conclusions did the authors reach about the research question? Did they generate new hypotheses? Do you agree with the conclusions? Do the results apply to the population in which you would be interested Do you accept the results of this study? Critical Appraisal using The Pocket Guide to Critical Appraisal Iain K. Crombie
BMJ THE STANDARD APPRAISAL QUESTIONS
ARE THE AIMS CLEARLY STATED? WAS THE SAMPLE SIZE JUSTIFIED? ARE THE MEASURMENTS LIKELY TO BE VALID AND RELIABLE? ARE THE STATISTICAL METHODS DESCRIBED? DID UNTOWARD EVENTS OCCUR DURING THE STUDY? WERE THE BASIC DATA ADEQUATELY DESCRIBED? DO THE NUMBERS ADD UP WAS THE STATISTICAL SIGNIFICANCE ASSESSED? WHAT DO THE MAIN FINDINGS MEAN? HOW IS NULL FINDINS INTERPRETED? ARE IMPORTANT EFFECTS OVERLOOKED? HOW DO THE RESULTS COMPARE WITH PREVIOUS REPORTS? WHAT IMPLICATIONS DOES THE STUDY HAVE FOR YOUR PRACTICE? THE COMPLETE LIST FOR APPRAISAL OF SURVEYS
The essential questions Who was studied? How was the sample obtained? What was the response rate?.
The detailed questions* Design Are the aims clearly stated? Is the design appropriate to the stated objectives? Was the sample size justified? Are the measurements likely to be valid and reliable? Are the statistical methods described? Is there a suggestion of haste? Conduct Did untoward events occur during the study?
Analysis Where the basic data adequately described? Do the numbers add up? Was the statistical significance assessed? Were the findings serendipitous?
Interpretation What do the main findings mean? How could selection bias arise? How are null findings interpreted? Are important effects overlooked? Can the results compare with previous reports? How do the results compare with previous reports? What implications does the study have for your practice? THE COMPLETE LIST FOR THE APPRAISAL OF COHORT STUDIES
The essential questions Who exactly has been studied? Was a control group used? Should one have been used? How adequate was the follow-up? The detailed questions* Design Are the aims clearly stated? Is the design appropriate to the stated aims? Was the sample size justified? Are the measurements likely to be valid and reliable? Were relevant outcome measures ignored? Are the statistical methods described? Conduct Did untoward events occur during the study? Analysis Did the analysis allow for the passage of time? Do the numbers add up? Were the basic data adequately described? Was statistical significance assessed? Interpretation What do the main findings mean? What else might influence the observed outcome? How are null findings interpreted? Are important effects overlooked? How do the results compare with previous reports? What implications does the study have for your practice? THE COMPLETE LIST FOR THE APPRAISAL OF CLINICAL TRIALS
The essential questions Were treatment randomly allocated? Were all the patients accounted for? Were outcomes assessed bind? The detailed questions* Design Are the aims clearly stated? Was the sample size justified? Are the measurements likely to be valid and reliable? Could the choice of subjects influence the size of treatment effect? Were the ambiguities in the description of the treatment and its administration? Are the statistical methods described? Could lack of blinding introduce bias? Are the outcomes clinically relevant? Conduct How was the randomization carried out? Did untoward events occur during the study? Analysis Were the treatment groups comparable at baseline? Were results analyzed by intention to treat? Was the statistical significance assessed? Were the basic data adequately described? Do the numbers add up? Were side-effect reported? Interpretation What do the main findings mean? How are null findings interpreted? Are important effects overlooked? How do the results compare with previous reports? What implications does the study have for your practice? THE COMPLETE LIST FOR THE APPRAISAL OF CASE-CONTROL STUDIES
The essential questions How were the cases obtained? Is the control group appropriate? Were data collected the same way for cases and controls? The detailed questions* Design Are the aims clearly stated? Is the method appropriate to the aims? Was the sample size justified? Are the measurements likely to be valid and reliable? Are the statistical methods described? Conduct Did untoward events occur during the study? Analysis Were the basic data adequately described? Do the numbers add up? Was there data-dredging? Was the statistical significance assessed? Interpretation What do the main findings mean? Where are the biases? Could there be confounding? How are null findings interpreted? Are important effects overlooked? How do the results compare with previous reports? What implications does the study have for your practice? THE COMPLETE LIST FOR APPRAISAL OF REVIEW PAPERS
The essential questions How were the papers identified? How was the quality of papers assessed? How were the results summarized? The detailed questions* Design Is the topic well defined? Are the statistical methods described? Conduct Were the detailed study designs reviewed? Was missing information sought? Analysis Were the basic data adequately described? Was publication bias taken into account? Was heterogeneity of effect investigated? Interpretation What do the main findings mean? Are there other findings which merit attention? Are the conclusions justified? How do the findings compare with previous reports? What implications does the study have for your practice? Evidence Based Medicine Evidence-based medicine (EBM) requires the integration of the best research evidence with our clinical expertise and our patients unique values and circumstances By best research evidence we mean valid and clinically relevant research, often from the basic sciences of medicine, but especially from patient-centered clinical research into the accuracy of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens. New evidence from clinical research both invalidates previously accepted diagnostic tests and treatments and replaces them with new ones that are more accurate, more efficacious, and safer Evidence Based Medicine By clinical expertise we mean the ability to use our clinical skills and past experience to rapidly identify each patients unique health state and prognosis, their individual risks and benefits of potential interventions, and their personal circumstances and expectations By patient values we mean the unique preferences, concerns and expectations each patient brings to a clinical encounter and which must be integrated into clinical decisions if they are to serve the patient. By patient circumstances we mean their individual clinical state and the clinical setting. Critical Appraisal using Evidence-Based Medicine. How to Practice and Teach EBM. Sharon E. Straus, W. Scott Richardson, Paul Glasziou, R. Brian Haynes.
Third edition (CD room); Elseiver Churchill Living stone
Critical Appraisal using EBM Version needs worksheets: 1. Diagnosis and screening worksheet 2. Harm / Etiology worksheet 3. Prognosis worksheet 4. Systematic Review worksheet 5. Therapy or Prevention worksheet 6. Etc
1. DIAGNOSIS WORKSHEET Are the results of this diagnostic study valid
Was there an independent , blind comparison with a reference (gold) Standard of diagnosis
Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom it would be used in practice)?
Was the reference standard applied regardless of the diagnostic test result?
Was the test (or cluster of tests) validated in a second, independent group of patients?
Diagnostic test result Positive a b a+b Negative c d c+d Totals a+c b+d a+b+c+d Can You apply this valid, important evidence about a diagnostic test in caring for your patient? Is the diagnostic test available, affordable, accurate, and precise in your setting? Can you generate a clinically sensible estimate of your patients pre-test probability (from personal experience, prevalence statistics, practice database, or primary studies)? Are the study patients similar to your own? Is it unlikely that the disease possibilities or probabilities have changed since the evidence was gathered? Can You apply this valid, important evidence about a diagnostic test in caring for your patient? Will the resulting post-test probabilities affect your management and help your patient? Could it move you across a test- treatment threshold ? Would your patient be a willing partner in carrying it out? Would the consequences of the test help your patient? Additional Notes: 2. HARM WORKSHEET
Are the results of this harm study valid? Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? Were treatments/exposures and clinical outcomes measured in the same ways in both groups (was the assessment of outcomes either objective or blinded to exposure)? Was the follow-up of study patients sufficiently long and complete? Do the results satisfy some diagnostic tests for caution? Are the results of this harm study valid? Is it clear that the exposure preceded the onset of the outcome? Is there a dose-response gradient? Is there positive evidence from a dechellenge-rechallenge study?
Is the association make biological sense?
Does the association make biological sense? What is the magnitude of the association between the exposure and outcome?
What is the precision of the estimate of the association between exposure and outcome Are the valid results from this harm study important? Adverse outcome
Totals Present (Case) Absent (control
Exposed to the treatment Yes (cohort) a b a+b No (cohort) c d c+d Totals a+c b+d a+b+c+d In randomized trial or cohort study: relative risk=RR=[a/(a+b)]/[c/(c+d)] In case-control study : odds ratio (or relative odds)=OR=ad/bc Should this valid, potentially important results changes the treatment of your patient? 1. Do the results apply to our patient? 2. Is our patient so different from those in the study that its results dont apply? 3. What are the patients risks of the adverse event? 4. To calculate the NNH ( number of patients we need to treat to harm one of them) for any odds ratio (OR) and our patients expected event rate for this adverse event if they were not exposed to this treatment (PEER): PEER (OR-1)+1 NNH = ------------------------------ PEER(OR-1)x(1-PEER) 5. What are our patients preferences, concerns and expectations from this treatment? 6. What alternative treatments are available? Additional notes:
3. PROGNOSIS WORKSHEET
Are the results of this prognosis study valid ?
1. Was a defined, representative sample of patients assembled at a common ( usually early) point in the course of their disease? 2. Was patient follow-up sufficiently long and complete? 3. Were objective outcome criteria applied in a blind fashion? 4. If subgroups with different prognoses are identified: - Was there adjustment for important prognostic factors? - Was there validation in an independent group (test set) of patients? Are the valid results of this prognosis study important? 1. How likely are the outcome over time? 2. How precise are the prognostic estimates? IF YOU WANT CALCULATE A CONFIDENCE INTERVAL AROUND THE MEASURE OF PROGNOSIS Clinical measure Standard error (SE) Typical calculation of CI Proportion ( as in the rate of some prognostic event, etc.) where: n=the number of patients P=the proportion of these patients who experience the event
__________ [p x (1-p)/n]
Where p is proportion and n is number of patients If p=24/60=0.4 (or40%) and n 60: _____________ SE =[0.4x(1-0.4)/60] = 0.063 (or 6.3%) 95%CI is 40%1.96x6.3% or 27.6% to 52.4 % n from your evidence: p from your evidence: Our calculation: SE: ___________ 95% CI: Can you apply this valid, important evidence about prognosis in caring for your patient? 1. Do the results apply to our patient? 2. Is our patient so different from those in the study that its results cannot apply? 3. Will this evidence make a clinically important impact on our conclusions about what to offer or tell our patient? Additional notes: 4. SYSTEMATIC REVIEW (OF THERAPY) WORKSHEET
Are the results of this systematic review valid?
1. Is this a systematic review of randomized trials? 2. Does it describe a comprehensive and detailed search for relevant trials? 3. Were the individual studies assessed for validity? 4. Were the individual patient data used in the analysis ( or aggregate data)? The numbers in the body of the tables are the NNTs for the corresponding odds ratio (OR) at that particular patients expected event rate (PEER)
Are the valid results of this systematic review important?
1. Are the results consistent across studies? 2. What is the magnitude of the treatment effect? 3. How precise is the treatment effect?
Translating odd ratio to NNTs
When the odds ratio (OR)<1 This table applies when a bad outcome is prevented by therapy
OR < 1
Patients expected event rate (PEER) 0.9 0.8 0.7 0.6 0.5 0.05 2.09 a 104 69 52 41 b 0.10 110 54 36 27 21 0.20 61 30 20 14 11 0.30 0.40 46 40 22 19 14 12 10 9 8 7 0.50 38 18 11 8 6 0.70 44 20 13 9 6 0.90 101 c 46 27 18 12 d a The relative risk reduction (RRR) here is 10% b The RRR here is 49% c For any OR, NTT is lowest when PEER=0.50 d The RRR here is 9%
When the odds ratio (OR)>1 This table applies both when a good outcome is increased by therapy and when a side effect is caused by therapy
OR > 1
Patients expected event rate (PEER) 1.1 1.2 1.3 1.4 1.5 0.05 212 106 71 54 43 0.10 112 57 38 29 23 0.20 64 33 22 17 14 0.30 49 25 17 13 11 0.40 0.50 43 42 23 22 16 15 12 12 10 10 0.70 51 27 19 15 13 0.90 121 66 47 38 32 Can you apply this valid, important evidence from systematic in caring for your patient ?
1. Do these results apply to our patient ? 2. Is our patient so different from those in the study that its results cannot apply? 3. Is the treatment feasible in our setting? 4. What are our patients potential benefits harms from the therapy? 5. Method I : In the OR tables above, find the intersection of the closest OR from the systematic review and our patients expected event rate (PEER) 6. Method II : To calculate the NNT from any OR and PEER
1-[PEERx(1-OR)] NNT= ---------------------------- (1-PEER)xPEERx(1-OR) 7. Are our patients values and preferences satisfied by the regimen and its consequences ? 8. Do we and our patient's have clear assessment of their values and preferences? 9. Are they met by this regimen and its consequences? Should you believe apparent qualitative differences in the efficacy of therapy in some subgroups of patients? Only if you can say yes to all of the following ? 1. Do they really make biologic and clinical sense? 2. Is the qualitative difference both clinically (beneficial for some but useless or harmful for others) and statistically significant? 3. Was this difference hypothesized before the study began (rather than the product of dredging the data)? 4. Was this one of just a few subgroup analyses carried out in this study? 5. Has the result been confirmed in other independent studies? Additional Notes: 5. THERAPY WORKSHEET Are the results of this single preventive or therapeutic trial valid?
1. Was the assignment of patients to treatments randomized? 2. Was the randomization list concealed? 3. Was follow-up of patients sufficiently long and complete? 4. Were all patients analyzed in the groups to which they were randomized? 5. Were patients, clinicians, and study personal kept" blind to treatment? 6. Were the groups treated equally, apart from the experimental treatment? 7. Were the groups similar at the start of the trial apart from the experimental therapy? Are the valid results of this randomized trial important?
1. What is the magnitude of the treatment effect? 2. How precise is the estimate of the treatment effect? SAMPLE CALCULATIONS Occurrence of diabetic neuropathy at 5 years among insulin-dependent diabetics in the DCCT trial Relative risk reduction (RRR) Absolute risk reduction (ARR) Number needed to treat (NNT) Usual insulin regimen control event rate (CER) Intensive insulin regimen experimental event rate (EER) CER EER CER CER - EER 1/ARR 9.6% 2.8% 9.6% - 2.8% 9.6% =71% 9.6% - 2.8% = 6.8 % 1/6.8% = 15 patients 95% CI a 4.4% to 9.2% 11 to 23 Are the valid results of this randomized trial important?
a 95% confidence interval (CI) on an NNT = 1/(limits on the CI of its ARR) CER x ( 1-CER) EER x (1-EER) = 1.96 ------------------------- + ----------------------------- number of control patients number of experimental patients
0.96 x 0.904 0.028 x 0.972 = 1.96 ----------------------- + --------------------- 730 711 = 2.4% YOUR CALCULATIONS Relative risk reduction (RRR) Absolute risk reduction (ARR) Number needed to treat (NNT) CER EER CER EER CER CER - EER 1/ARR 95% CI Can you apply this valid, important evidence about therapy in caring for your patient ?
1. Do these results apply to our patient ? 2. Is our patient so different from those in the study that its results cannot apply? 3. Is the treatment feasible in our setting? 4. What are our patients potential benefits harms from the therapy? 5. Method I : f Risk of the outcome in our patient, relative to patients in the trial Expressed as a decimal: __________ NNT/f = ---------/--------------= (NNT for patients like ours) 6. Method II : 1/(PEER xRRR) Our patients expected event rate if they received the control treatment (PEER)= ___ 1/(PEER x RRR) = 1/ = (NNT for patients like ours) 7. Are our patients values and preferences satisfied by the regimen and its consequences ? 8. Do we and our patients have a clear assessment of their values and preferences? 9. Are they met by this regimen and its consequences?
Additional notes: RINGKASAN
Setelah membaca artikel dan belum jelas desain penelitiannya (study design dasar), maka worksheet yang digunakan adalah: I.1. Critical appraisal worksheet 1991, Epidemiology A Basic Methods
Setelah membaca artikel dan telah jelas desain penelitiannya (study design dasar), maka menggunakan The Pocket Guide to Critical Appraisal By IAIN K.Crombie dengan worksheet: II.1. The complete list for the appraisal of surveys (p:35) II.2. The complete list for the appraisal of cohort studies (p:42) II.3. The complete list for the appraisal of clinical trials (p:49) II.4. The complete list for the appraisal of case-control studies (p:55) II.5. The complete list for the appraisal of review papers (p:62) II.6. Baik point II.1 s/d I.5. perlu jawaban pertanyaan &..dari I.3.1 I.3.3
RINGKASAN
Setelah membaca artikel dan telah jelas desain dan jenis penelitiannya maka menggunakan format EBM yang terdiri dari: III.1 Diagnosis and screening III.2 Harm / Etiology III.3 Prognosis III.4 Therapy or Prevention III.5 Etc
The conclusions have to answer these questions: 1. Is the evidence from this study valid? 2. If valid, is this evidence important? 3. If valid and important, can you apply this evidence in caring for your patients
RINGKASAN
DAFTAR PUSTAKA
1. Critical Appraisal ( Including Study Terminology). Epidemiology a Basic Methods. Critical Appraisal ( Including Study Terminology). Newcastle: University of Newcastle; 1994. p.12 2. Crombie IK. The Pocket Guide to Critical Appraisal: A Handbook for Health Care Professionals. London: BMJ Publising group; 1996. p.23, 35, 42, 49, 62 3. Straus SE, Richardson WS,Glaziou P, Haynes RB. Evidence Based Medicine: How to Practice and Teach EBM 3 rd ed CD room; Elseiver Churchill Living stone GLOSSARY Terms you are likely to encounter in your clinical reading Absolute risk reduction (ARR). See treatment effects Allocation concealment. Occurs when the person who is enrolling a participant into a clinical trial is unaware whether the next participant to be enrolling will be allocated to the intervention or control group Case-control study. A study which involves identifying patients who have the outcome of interest (cases) and control patients without the same outcome, and looking back to see if they had the exposure of interest Case series. A report on a series of patients with an outcome of interest. No control group is involved Clinical practice guideline. A systematically developed statement designed to assist clinician and patient decisions about appropriate health care for specific clinical circumstances Cohort study. Involves identification of two groups (cohort) of patients, one that received the exposure of interest, and one that did not, and following these cohorts forward for they outcome of interest. Confidence interval (CI). Quantifies the uncertainly in measurement. It is usually reported as 95% CI, which is the range of values within which we can be 95% sure that the true value for the whole population lies. For example, for an NNT of 10 with a 95% CI or 5 to 15, we would have 95% confidence that the true NNT values lies between 5 and 15 Control event rate (CER). See treatment effects Cost- benefit analysis. Assesses whether the cost of an intervention as worth the benefit measuring both in the same units; monetary units are usually used Cost-minimization analysis. If health effects are known to be equal, only costs are analyzed and the least costly alternative is chosen
Cost-utility analysis. Converts health effects into personal preferences (or sterilities) and describes how much it costs for some additional quality gain(e.q. cost per additional quality gain (e.q. cost per additional quality-adjusted life-year, or QALY) Crossover study design. The administration of two or more experimental therapies one after the other in a specified or random order to the same group of patients Cross-sectional study, The observation of defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously Decision analysis ( or clinical decision analysis). The application of explicit, quantitative methods that quantity prognoses, treatment effects, and patient values in order to analyze a decision under conditions of uncertainty
Event rate. The proportion of patients in a group in whom the event is observed. Thus, if of 100 patients, the event is observed in 27, the event rate is 0.27. Control event rate(CER) and experimental event rate (EER) are used to refer to this in control and experimental groups of patients, respectively. The patient expected event rate (PEER) refers to the rate of events we'd expect in a patient who received no treatment or conventional treatment. See treatment effects. Evidence-based health care. Extends the application of the principles of evidence-based medicine (see below) to all professions associated with health care, including purchasing management. Evidence-based medicine (EBM). The conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine requires the integration of individual clinical expertise with the best available external clinical evidence from systematic research and our patients unique values and circumstances. Experimental event rate (EER). See treatment effects. Inception cohort. A group of patients who are assembled near the onset of the target disorder Incidence The proportion of new cases of the target disorder in the population at risk a specified time interval. Intention-to-treat analysis. A method of analysis for randomized trials in which all randomly assigned to one of the treatments are analyzed together, regardless of or not they completed or received that treatment, in order to preserve randomization. Likelihood ratio (LR). The likelihood that a given test result would be expected in a patient with the target disorder compared with the likelihood that the same result would be expected in a patient without the target disorder. See Table A2.2 for calculations. Meta-analysis. A systematic review that uses quantitative methods to synthesize and e the results. n-of-1-trials. In such trials, the patient undergoes pairs of treatment periods organized so that one period involves the use of the experimental treatment and the other involves the use of an alternate or placebo therapy. The patient and physician are blinded, if possible, and outcomes are monitored. Treatment periods are replicated until the clinician and patient are convinced that the treatments are definitely different or definitely not different. Negative predictive value. Proportion of people with a negative test who are free of the target disorder. See also likelihood ratio. needed to treat (NNT). The inverse of the absolute risk reduction and the number of patients that need to be treated to prevent one bad outcome. See treatment effects Odds. A ratio of the number of people incurring an event to the number of people who have an event. Odds ratio (OR). The ratio of the odds of having the target disorder in the experimental group relative to the odds in favor of having the target disorder in the control group (in cohort studies or systematic reviews), or the odds in favor of being exposed in participants with target disorder divided by the odds in favor of being exposed in control participants (without the target disorder). See Table A2A for calculations. Overview. See systematic review. Patient expected event rate (PEER). See treatment effects. Positive predictive value. Proportion of people with a positive test who have the targ disorder. See also likelihood ratio. Post-test odds. The odds that the patient has the target disorder after the test is carried out [(pre-test odds) x (likelihood )] Post-test probability. The proportion of patients with that particular test result who have the target disorder [(post-test odds) / (1 + post-test odds)]. Pre-test odds. The odds that the patient has the target disorder before the test is carried out [(pre-test probability) / (1 - pre-test probability)]. Pre-test probability/prevalence. The proportion of people with the target disorder in the population at risk at a specific time (point prevalence) or time interval (period prevalence). See also likelihood ratio. Randomization (or random allocation). Method analogous to tossing a coin to assign patients to treatment groups (the experimental treatment is assigned if the coin lands "heads"; a conventional, "control" or "placebo" treatment is given if the coin lands "tails Randomized controlled clinical trial (RCT). Participants are randomly allocated into an- experimental group or a control group and followed over time for the variables/outcomes of interest. Relative risk reduction (RRR). See treatment effects. Risk ratio (RR). The ratio of the risk in the treated group (EER) to the risk in the control group (CER); used in randomized trials and cohort studies. RR=ERR/CER. Also called relative risk. Sensitivity. Proportion of people with the target disorder who have a positive test result. It is used to assist in assessing and selecting a diagnostic test/sign/symptom. See also likehood ratio. SnNout. When a sign/test/symptom has a high sensitivity (5n), a negative result (N) can help rule out (out) the diagnosis. For example, the sensitivity of a history of ankle swelling for diagnosing ascites is 93%; therefore, if person does not have a history of ankle swelling, it is highly unlikely that the person has ascites. Specificity. Proportion of people without the target disorder who have a negative test result. It is used to assist in assessing and selecting a diagnostic test/sign/symptom, See also likelihood ratio. SpPin. When a sign/test/symptom has a high specificity (Sp), a positive result (P) can help to rule in (in) the diagnosis. For example, the specificity of a fluid wave for diagnosing ascites is 92%; therefore, if a person does have a fluid wave, he/she may have ascites. Systematic review. A summary of the medical literature that uses explicit methods to perform a comprehensive literature search and critical appraisal of individual studies, and that uses appropriate statistical techniques to combine these valid studies. Treatment effects. The evidence-based journals (Evidence Based Medicine and ACP journal Club) have achieved consensus on some of the terms they use to describe both the good and the bad effects of therapy. We will bring them to life with a synthesis of three randomized trials in diabetes which individually showed that several years of intensive insulin therapy reduced the proportion of patients with worsening retinopathy to 13% from 38, raised the proportion of patients with satisfactory hemoglobin A 1c levels to 60% from about 30%, and increased the proportion of patients with at least one episode of symptomatic hypoglycemia to 57% from 23%. Note that, in each case, the first number constitutes the "experimental event rate" (EER), and the second number the "control event rate" (CER). We will use the following terms and calculations to describe these effects treatment. When the experimental treatment reduces the probability of a bad outcome (worsening - diabetic retinopathy) RRR (relative risk reduction). The proportional reduction in rates of bad outcomes between experimental and control participants in a trial, calculated as [EER CER]/CER accompanied by a 95% confidence interval (CI). In the case of worsening diabetic retinopathy, [EER CER]/CER = [13% - 38%]/38% = 66%. AAR (absolute risk reduction). The absolute arithmetic difference in rates of bad outcomes between experimental and control participants in a trial, calculated as [EER CER], and accompanied by a 95% CI. In this case, [EER CER] = [13% - 38%] = 25(This sometimes called the risk difference.) NNT (number needed to treat). The number of patients who need to be treated to achieve one additional favorable outcome, calculated as l/ARR and accompanied by a 95% CI. In this case, 1/ARR = 1/25% = 4. when the experimental treatment increases the probability of a good outcome (satisfactory hemoglobin A 1c levels) RBI (relative benefit increase). The proportional increase in rates of good outcomes between experimental and control patients in a trial, calculated as [EER CER]/CER, and accompanied by a 95% confidence interval (CI). In the case of satisfactory hemoglobin A 1c levels, [EER CER]/CER = [60% - 30%]/30% = 100%. ABI (absolute benefit increase). The absolute arithmetic difference in rates of good outcomes between experimental and control patients in a trial, calculated as [EER CER], and accompanied by a 95% CI. In the case of satisfactory hemoglobin A 1c levels, [EER CER]= [60% - 30%]= 30% NNT (number needed to treat). The number of patients who need to be treated to achieve one additional good outcome, calculated as 1/ARR and accompanied by a 95% C is case, 1/ARR = 1/30% = 3. When the experimental treatment increases the probability of a bad outcome (episodes of hypoglycemia)) RRI (relative risk increase). The proportional increase in rates of bad outcomes between experimental and control patients in a trial, calculated as [EER CER]/ CER, and accompanied by a 95% confidence interval (CI). In the case of hypoglycemic episodes, [EER-CER] = [57% - 23% ]/ 23% = 148%. (RRI is also used in assessing the impact of "risk factors" for disease.) ARI (absolute risk increase). The absolute arithmetic difference in rates of bad outcomes between experimental and control patients in a trial, calculated as [EER CER], and accompanied by a 95% C1. In the case of hypoglycemic episodes, [EER CER] = [57% - 23%] = 34%. (ARI is also used in assessing the impact of "risk factors" for disease.) NNH (number needed to harm). The number of patients who, if they received the experimental treatment, would result in one additional patient being harmed, compared with patients who received the control treatment; calculated as I/AAR and accompanied by a 95% CI. In the case, 1/ARR=1/34% =3
Table A2.1 How to calculate LRs
Table A2.2 We can assume that there are four possible groups of patients, as indicated ( a to d ) in the table. From these we can determine the sensitivity and specificity as follows: Sensitivity = a/(a + c) Specificity = d/ (b + d) We can now use these to calculate the likelihood ratio for a positive test result (LR+): LR+ = sensitivity/ (1 specificity) = [a/(a +c)]/[b/(b+d)] Similarly, we can calculate the likelihood ratio for a negative test result (LR-): LR - = (1-sensitivity)/specificity = [c/(a+c)]/[d/(b+d)] Positive predictive value = a/(a+b) Negative predictive value = d/(c+d) Pre-test probability = (a+c)/(a+b+c+d) SAMPLE CALCULATION
Suppose you have a patient with anemia and a serum feritin of 60 mmol/L You come across a systematic review* of serum ferritin as a diagnostic test for iron deficiency anemia, with the results summarized in the following table.
Table A2.3 The results indicate that 90% or the patients with iron deficiency anemia have a positive test result (serum ferritin < 65 mmol/L). This is known as the sensitivity and is calculated as:
Sensitivity = a/(a+c) = 731/809 = 90%
The results also show that 85% of patients who do not have iron deficiency anemia have a negative test result. This is referred to as the specificity, calculated as:
Spesitivity = d/(b+d) = 1500/1770 = 85%
From the sensitivity and specificity, the positive (LR+) and negative (LR-) likelhood ratios can be determinated
The results indicate that 90% or the patients with iron deficiency anemia have a positive test result (serum ferritin < 65 mmol/L). This is known as the sensitivity and is calculated as:
Sensitivity = a/(a+c) = 731/809 = 90%
The results also show that 85% of patients who do not have iron deficiency anemia have a negative test result. This is referred to as the specificity, calculated as:
Spesitivity = d/(b+d) = 1500/1770 = 85%
From the sensitivity and specificity, the positive (LR+) and negative (LR-) likelhood ratios can be determinated
Thus from your calculation of LR+, you determine that your patients positive test result would be about six times more likely to be seen in someone with iron deficiency anemia than in someone without the disorder.
Calculation of odds ratio/relative risk
The table below can be used to calculate the odds ratio/relative risk for the use of trimethoprim- sulfamethoxazole prophylaxis in cirrhosis:
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