Steps The steps for designing explicit, evidence-based guidelines were described in the late 1980s: formulate the question (population, intervention, comparison intervention, outcomes, time horizon, setting); search the literature to identify studies that inform the question; interpret each study to determine precisely what it says about the question; if several studies address the question, synthesize their results (meta-analysis); summarize the evidence in evidence tables; compare the benefits, harms and costs in a balance sheet; draw a conclusion about the preferred practice; write the guideline; write the rationale for the guideline; have others review each of the previous steps; implement the guideline. For the purposes of medical education and individual-level decision making, five steps of<unk>  in practice were described in 1992 and the experience of delegates attending the 2003 Conference of Evidence-Based Health Care Teachers and Developers was summarized into five steps and published in 2005. This five-step process can broadly be categorized as follows: # Translation of uncertainty to an answerable question; includes critical questioning, study design and levels of evidence # Systematic retrieval of the best evidence available # Critical appraisal of evidence for internal validity that can be broken down into aspects regarding: #* Systematic errors as a result of selection bias, information bias and confounding #* Quantitative aspects of diagnosis and treatment #* The effect size and aspects regarding its precision #* Clinical importance of results #* External validity or generalizability # Application of results in practice # Evaluation of performance Evidence reviews Systematic reviews of published research studies are a major part of the evaluation of particular treatments. The Cochrane Collaboration is one of the best-known organisations that conducts systematic reviews. Like other producers of systematic reviews, it requires authors to provide a detailed study protocol as well as a reproducible plan of their literature search and evaluations of the evidence. After the best evidence is assessed, treatment is categorized as (1) likely to be beneficial, (2) likely to be harmful, or (3) without evidence to support either benefit or harm. A 2007 analysis of 1,016 systematic reviews from all 50 Cochrane Collaboration Review Groups found that 44% of the reviews concluded that the intervention was likely to be beneficial, 7% concluded that the intervention was likely to be harmful, and 49% concluded that evidence did not support either benefit or harm. 96% recommended further research. In 2017, a study assessed the role of systematic reviews produced by Cochrane Collaboration to inform US private payers' policymaking; it showed that although the medical policy documents of major US private payers were informed by Cochrane systematic reviews, there was still scope to encourage the further use. Assessing the quality of evidence<unk>  categorizes different types of clinical evidence and rates or grades them according to the strength of their freedom from the various biases that beset medical research. For example, the strongest evidence for therapeutic interventions is provided by systematic review of randomized, well-blinded, placebo-controlled trials with allocation concealment and complete follow-up involving a homogeneous patient population and medical condition. In contrast, patient testimonials, case reports, and even expert opinion have little value as proof because of the placebo effect, the biases inherent in observation and reporting of cases, and difficulties in ascertaining who is an expert (however, some critics have argued that expert opinion "does not belong in the rankings of the quality of empirical evidence because it does not represent a form of empirical evidence" and continue that "expert opinion would seem to be a separate, complex type of knowledge that would not fit into hierarchies otherwise limited to empirical evidence alone."). Several organizations have developed grading systems for assessing the quality of evidence. For example, in 1989 the U.S. Preventive Services Task Force (USPSTF) put forth the following system: * Level I: Evidence obtained from at least one properly designed randomized controlled trial. * Level II-1: Evidence obtained from well-designed controlled trials without randomization. * Level II-2: Evidence obtained from well-designed cohort studies or case-control studies, preferably from more than one center or research group. * Level II-3: Evidence obtained from multiple time series designs with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. * Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Another example are the Oxford CEBM Levels of Evidence published by the Centre for<unk> . First released in September 2000, the Levels of Evidence provide a way to rank evidence for claims about prognosis, diagnosis, treatment benefits, treatment harms, and screening, which most grading schemes do not address. The original CEBM Levels were Evidence-Based On Call to make the process of finding evidence feasible and its results explicit. In 2011, an international team redesigned the Oxford CEBM Levels to make them more understandable and to take into account recent developments in evidence ranking schemes. The Oxford CEBM Levels of Evidence have been used by patients and clinicians, as well as by experts to develop clinical guidelines, such as recommendations for the optimal use of phototherapy and topical therapy in psoriasis and guidelines for the use of the BCLC staging system for diagnosing and monitoring hepatocellular carcinoma in Canada. In 2000, a system was developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The GRADE system takes into account more dimensions than just the quality of medical research. It requires users who are performing an assessment of the quality of evidence, usually as part of a systematic review, to consider the impact of different factors on their confidence in the results. Authors of GRADE tables assign one of four levels to evaluate the quality of evidence, on the basis of their confidence that the observed effect (a numeric value) is close to the true effect. The confidence value is based on judgments assigned in five different domains in a structured manner. The GRADE working group defines 'quality of evidence' and 'strength of recommendations' based on the quality as two different concepts that are commonly confused with each other. Systematic reviews may include randomized controlled trials that have low risk of bias, or observational studies that have high risk of bias. In the case of randomized controlled trials, the quality of evidence is high but can be downgraded in five different domains. * Risk of bias: A judgment made on the basis of the chance that bias in included studies has influenced the estimate of effect. * Imprecision: A judgment made on the basis of the chance that the observed estimate of effect could change completely. * Indirectness: A judgment made on the basis of the differences in characteristics of how the study was conducted and how the results are actually going to be applied. * Inconsistency: A judgment made on the basis of the variability of results across the included studies. * Publication bias: A judgment made on the basis of the question whether all the research evidence has been taken to account. In the case of observational studies per GRADE, the quality of evidence starts off lower and may be upgraded in three domains in addition to being subject to downgrading. * Large effect: Methodologically strong studies show that the observed effect is so large that the probability of it changing completely is less likely. * Plausible confounding would change the effect: Despite the presence of a possible confounding factor that is expected to reduce the observed effect, the effect estimate still shows significant effect. * Dose response gradient: The intervention used becomes more effective with increasing dose. This suggests that a further increase will likely bring about more effect. Meaning of the levels of quality of evidence as per GRADE: * High Quality Evidence: The authors are very confident that the presented estimate lies very close to the true value. In other words, the probability is very low that further research will completely change the presented conclusions. * Moderate Quality Evidence: The authors are confident that the presented estimate lies close to the true value, but it is also possible that it may be substantially different. In other words, further research may completely change the conclusions. * Low Quality Evidence: The authors are not confident in the effect estimate, and the true value may be substantially different. In other words, further research is likely to change the presented conclusions completely. * Very Low Quality Evidence: The authors do not have any confidence in the estimate and it is likely that the true value is substantially different from it. In other words, new research will probably change the presented conclusions completely. Categories of recommendations In guidelines and other publications, recommendation for a clinical service is classified by the balance of risk versus benefit and the level of evidence on which this information is based. The U.S. Preventive Services Task Force uses the following system: * Level A: Good scientific evidence suggests that the benefits of the clinical service substantially outweigh the potential risks. Clinicians should discuss the
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