evidence-based medicine

Systematic Review – Defining the Question

March 18, 2018 Evidence-Based Medicine, Research No comments , , , ,

Eligibility Criteria

The acronym PICO helps to serve as a reminder of the essential components of review question. One of the features that distinguish a systematic review from a narrative review is the pre-specification of criteria for including and excluding studies in the review (eligibility criteria). Eligibility criteria are  a combination of aspects of the clinical question plus specification of the types of studies that have addressed these questions. The participants, interventions and comparisons in the clinical question usually translate directly into eligibility criteria for the review. Outcomes usually are not part of the criteria for including studies: a Cochrane review would typically seek all rigorous studies of a particular comparison of interventions in a particular population of participants, irrespective of the outcomes measured or reported. However, some reviews do legitimately restrict eligibly to specific outcomes.

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The criteria for considering types of people included in studies in a review should be sufficiently broad to encompass the likely diversity of studies, but sufficiently narrow to ensure that a meaningful answer can be obtained when studies are considered in aggregate. It is often helpful to consider the types of people that are of interest in two steps. First, the diseases or conditions of interest should be defined using explicit criteria for establishing their presence or not. Criteria that will force unnecessary exclusion of studies should be avoided. For example, diagnostic criteria that were developed more recently – which may be viewed as the current gold standard for diagnosing the condition of interest – will not have been used in earlier studies. Expensive or recent diagnostic tests may not be available in many countries or settings.

Second, the broad population and setting of interest should be defined. This involves deciding whether a special population group is of interest, determined by factors such as age, sex, race, educational status or the presence of a particular condition such as angina or shortness of breath. Interest may focus on a particular settings such as a community, hospital, nursing home, chronic care institution, or outpatient setting.

The types of participants of interest usually determine directly the participant-related eligibility criteria for including studies. However, pre-specification of rules for dealing with studies that only partially address the population of interest can be challenging.

Any restrictions with respect to specific population characteristics or settings should be based on a sound rationale. Focusing a review on a particular subgroup of people on the basis of their age, sex or ethnicity simply because of personal interests when there is no underlying biologic or sociological justification for doing so should be avoided.


The second key component of a well-formulated question is to specify the interventions of interest and the interventions against which these will be compared (comparisons). In particular, are the interventions to be compared with an inactive control intervention, or with an active control intervention? When specifying drug interventions, factors such as the drug preparation, route of administration, dose, duration, and frequency should be considered. For more complex interventions (such as educational or behavioral interventions), the common or core features of the interventions will need to be defined. In general, it is useful to consider exactly what is delivered, at what intensity, how often it is delivered, who delivers it, and whether people involved in delivery of the intervention need to be trained. Review authors should also consider whether variation in the intervention (i.e., based on dosage/intensity, mode of delivery, frequency, duration etc) is so great that it would have substantially different effects on the participants and outcomes of interest, and hence may be important to restrict.


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Although reporting of outcomes should rarely determine eligibility of studies for a review, the third key component of a well-formulated question is the delineation of particular outcomes that are of interest. In general, Cochrane reviews should include all outcomes that are likely to be meaningful to clinicians, patients, the general public, administrators and policy makers, but should not include outcomes reported in included studies if they are trivial or meaningless to decision makers. Outcomes considered to be meaningful and therefore addressed in a review will not necessarily have been reported in individual studies. For example, quality of life is an important outcome, perhaps the most important outcome, for people considering whether or not to use chemotherapy for advanced cancer, even if the available studies are found to report only survival. Including all important outcomes in a review will highlight gaps in the primary research and encourage researchers to address these gaps in future studies.

Outcomes may include survival (mortality), clinical events (e.g., strokes or myocardial infarction), patient-reported outcomes (e.g., symptoms, quality of life), adverse events, burdens (e.g., demands on caregivers, frequency of tests, restrictions on lifestyle) and economic outcomes (e.g., cost and resource use). It is critical that outcomes used to assess adverse effects as well as outcomes used to assess beneficial effects are among those addressed by a review. If combinations of outcomes will be considered, these need to be specified. For example, if a study fails to make a distinction between non-fatal and fatal strokes, will these data be included in a meta-analysis if the question specifically related to stroke death?

Review authors should consider how outcomes may be measured, both in terms of the type of scale likely to be used and the timing of measurement. Outcomes may be measured objectively (e.g., blood pressure, number of strokes) or subjectively as rated by a clinical, patient, or carer (e.g., disability scales). It may be important to specify whether measurement scales have been published or validated. When defining the timing of outcome measurement, authors may consider whether all time frames or only selected time-points will be included in the review. One strategy is to group time-points into pre-specified intervals to represent “short-term”, “medium-term” and “long-term” outcomes and to take no more than one of each from each study for any particular outcome. It is important to give the timing of outcome measure considerable thought as it can influence the results of the review.

While all important outcomes should be included in Cochrane reviews, trivial outcomes should not be included. Authors need to avoid overwhelming and potentially misleading readers with data that are of little or no importance. In addition, indirect or surrogate outcome measures, such as laboratory results or radiologic results, are potentially misleading and should be avoided or interpreted with caution because they may not predict clinically important outcomes accurately. Surrogate outcomes may provide information on how a treatment might work but not whether it actually does work. Many interventions reduce the risk for a surrogate outcome but have no effect or have harmful effects on clinically relevant outcomes, and some interventions have no effect on surrogate measures but improve clinical outcomes.Screen Shot 2018 03 18 at 6 49 15 PM

Main Outcomes

Once a full list of relevant outcomes has been complied for the review, authors should prioritize the outcomes and select the main outcomes of relevance to the review question. The main outcomes are the essential outcomes for decision-making, and are those that would form the basis of a “Summary of findings” table. “Summary of findings” tables provide key information about the amount of evidence for important comparisons and outcomes, the quality of the evidence and the magnitude of effect. There should be no more than seven main outcomes, which should generally not include surrogate or interim outcomes. They should not be chosen on the basis of any anticipated or observed magnitude of effect, or because they are likely to have been addressed in the studies to be reviewed.

Primary Outcomes

Primary outcomes for the review should be identified from among the main outcomes. Primary outcomes are the outcomes that would be expected to be analyzed should the review identify relevant studies, and conclusions about the effects of the interventions under review will be based largely on these outcomes. There should in general be no more than three primary outcomes and they should include at least one desirable and at least one undesirable outcome (to assess beneficial and adverse effects respectively).

Secondary Outcomes

Main outcomes not selected as primary outcomes would be expected to be listed as secondary outcomes. In addition, secondary outcomes may include a limited number of additional outcomes the review intends to address. These may be specific to only some comparisons in the review. For example, laboratory tests and other surrogate measures may not be considered as main outcomes as they are less important than clinical endpoints in informing decisions, but they may be helpful in explaining effect or determining intervention integrity.

Types of Study

Certain study designs are more appropriate than others for answering particular questions. Authors should consider a priori what study designs are likely to provide reliable data with which to address the objectives of their review.

Because Cochrane reviews address questions about the effects of health care, they focus primarily on randomized trials. Randomization is the only way to prevent systematic differences between baseline characteristics of participants in different intervention groups in terms of both known and unknown (or unmeasured) confounders. For clinical interventions, deciding who receives an intervention and who does not is influenced by many factors, including prognostic factors. Empirical evidence suggests that, on average, non-randomized studies produce effect estimates that indicate more extreme benefits of the effects of health care than randomized trials. However, the extent, and even the direction, of the bias is difficult to predict.

Specific aspects of study design and conduct should also be considered when defining eligibility criteria, even if the review is restricted to randomized trials. For example, decisions over whether cluster-randomized trials and cross-over trials are eligible should be made, as should thresholds for eligibility based on aspects such as use of a placebo comparison group, evaluation of outcomes blinded to allocation, or a minimum period of follow-up. There will always be a trade-off between restrictive study design criteria (which might result in the inclusion of studies with low risk of bias, but which are very small in number) and more liberal design criteria (which might result in the inclusion of more studies, but which are at a higher risk of bias). Furthermore, excessively broad criteria might result in the inclusion of misleading evidence. If, for example, interest focuses on whether a therapy improves survival in patients with a chronic condition, it might be inappropriate to look at studies of very short duration, except to make explicit the point that they cannot address the question of interest.

Scope of Review Question

The questions addressed by a review may be broad or narrow in scope. For example, a review might address a broad question regarding whether anti platelet agents in general are effective in preventing all thrombotic events in humans. Alternatively, a review might address whether a particular anti platelet agent, such as aspirin, is effective in decreasing the risk of a particular thrombotic event, stroke, in elderly persons with a previous history of stroke.

Determining the scope of a review question is a decision dependent upon multiple factors including perspectives regarding a question’s relevance and potential impact; supporting theoretical, biologic and epidemiological information; the potential generalizability and validity of answers to the questions; and available resources.

The Process of Differential Diagnosis

May 24, 2017 Uncategorized No comments , , , , ,

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Elements of the Differential Diagnosis

Decision-making on the Basis of Diagnosis. The physician endeavors to organize the subjective complaints and the objective findings of a patient in order to receive further indications to proceed. This approach is frequently chosen because a diagnosis in the conventional sense is not always easy to make, as more than one diagnosis can often be possible at the same time. Therefore, an important first step is to create a list of problems with a detail description.

Dynamics of Reaching a Diagnosis. The diagnosis is of utmost importance not only for the prognosis but also for the introduction of an appropriate therapy. An established diagnosis always needs to be reassessed. Secondary diseases, complications, and side-effects can supervene. Each diagnosis continues to be a differential diagnosis, since the particular symptoms, even during the course of a disease, have to be continually reevaluated, carefully considered, and differentiated. For a proper evaluation of the symptoms and risk factors, knowledge of their clinical meaning is crucial. Consequently, the purpose of differential diagnosis is to point out what disease can occur, when specific symptoms appear, and what risk factors with the utmost probability accompany specific diseases. In most cases, there are numerous possibilities and additional factors that have to be taken into account. Exclusively listing all the possibilities would not be beneficial.

Practical Procedure for Establishing a Diagnosis

The diagnosis is based on four essential aspects:

  • medical history
  • state of health
  • laboratory and other investigations
  • monitoring

In case of an unsolved disease, the number of possible remaining diagnoses can be reduced drastically via history-taking and clinical examination. The additional morphological, physical, chemical, and biological examinations allow the isolation of the most probable diagnosis. Monitoring is a critical quality control of the previous diagnostic process, as well as the subsequent therapeutic decisions.

Cardinal Symptoms. In differential diagnosis we proceed from a single dominant symptom, or group of symptoms or main symptoms, and try to classify as much as possible on the basis of the current research, in order to obtain a clinical picture. In most cases, a differential diagnosis is considered when a cardinal symptom indicates the direction of further measures. This leading symptom can emerge from the medical history, from clinical findings, as well as from laboratory work results. So-called problem-oriented patient care is practiced in a similar manner.

Correct Evaluation of Evident Findings and the Differential Diagnosis

Process of Clinical Judgement. The correct evaluation of findings is crucial for the diagnosis. Positive and negative predictive values play important roles in this context. Nevertheless, personal intuition with regard to the individual patient remains an important factor.

Pathognomonic symptoms or combinations of symptoms are rare, but must be recognized when present. Except in the most obvious cases, we are subject to continuous uncertainty in everyday clinical life – we must use the available resources to decide on the most probable diagnosis for our individual patients and select the most effective treatment. It is assumed that with additional clinical experience the correct clinical judgement will automatically be made. In this we are supported by studies that critically analyze individual investigative steps and diagnostic processes. Guidelines which critically assess current research and place it in context are often helpful.

Probability-based Decision Analysis. In cases of ambiguous and usually complex situations, the physician can decrease the probability of error when diagnosing or excluding a disease using reasoning based on decision analysis. He or she analyses the probability of a disease diagnosis on the basis of the findings (post-test probability), whereby both the sensitivity and specificity of the test must be given, as well as considering the pretest probability (current probability).

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Diagnostic Process. The path from unspecified disease to definitive diagnosis is only rarely a linear one by which data are first collected and then analyzed according to established criteria. Additional examinations are to be conducted as indicated, whereupon everything is reevaluated in order to make a definite diagnosis. Frequently, only a few minutes into a medical discussion, first working hypotheses are formulated that ultimately direct further history-taking and examination.

Preliminary Diagnosis and Immediate Therapeutic Consequences. The first impression is on the one hand crucial, but on the other hand can be dangerous if not continually challenged by results of ongoing examinations. It is essential to recognize serious disease as early as possible, and to quickly initiate the appropriate measures, which are often vital to the prognosis. During the diagnostic process it is therefore often necessary to introduce therapeutic measures without a firm diagnosis, and independent of the specific etiology. Treatment on the basis of a preliminary diagnosis is often acceptable for most common diseases.

In cases of new symptoms or an “atypical” course of disease, the diagnosis should be challenged. The following possibilities must be considered:

  • The first diagnosis was wrong
  • The diagnosis was correct, a complication supervened
  • The diagnosis was correct, a secondary independent disease supervened
  • The diagnosis was correct, side effects from therapy occurred
  • The diagnosis was correct and the course of the disease is indeed atypical

Factors that Can Influence the Differential Diagnostic Thought Process

Prevalence of Disease

Differential diagnosis is based on the knowledge as to which symptoms and disease are common. According to an American study involving over 300 million cases of consultations in private practices of internists, the most common complaints are: abdominal pain, thoracic pain, back pain, headaches, fatigue, coughing and catarrhal symptoms, as well as leg pain, skin symptoms, and vertigo.

Differential diagnosis also takes into account the frequency of diseases according to the overall situation.


The influence of age must always be considered. Knowledge of age distribution provides valuable clues for the diagnosis.


Some diseases occur more frequently in males than in females, and vice versa. This is especially true for occupational diseases as well as diseases caused by smoking or alcohol. Because on their anatomic configuration, women are susceptible to reoccurring urinary tract infections, pyelonephritis and iron deficiency due to menorrhea.


Lifestyle is very important to people today. Some positive habits are healthy nutrition and fitness; harmful habits include addictive behaviors. The influence of alcohol especially on the liver, blood pressure, and nervous system is well known. Smoking, which is particularly on the rise in adolescents, is responsible for the emergence of vascular diseases as well as pulmonary diseases.

Eating Habits

Eating habits are at least partly responsible for many diseases. To a large extent, obesity is closely associated with disease. Diabetes mellitus type 2, arthrosis, and hypertension are more frequently observed in obese persons. Obesity is one of the risk factors in the development of arteriosclerosis and its consequences. Also the influence of eating habits with regard to malignant tumors is suggested.

Season, Time of Day, and Weather

Certain diseases are clearly dependent on the season:

  • Food-associated infectious diseases in particular, e.g., salmonellosis, occur more frequently in warm seasons.
  • The seasonal emergence of allergic coryza depends on airborne pollens (spring/summer)
  • Respiratory infections occur more frequently during the winter months and cause higher morbidity and mortality in the elderly population, especially in a humid climate and after sudden changes of weather (influenza, respiratory syncytial virus).

Circadian rhythms also plays a role. Chronic polyarthritis is a disease with an explicit circadian rhythm and reaches maximum activity in the early morning and a minimum of activity in the afternoon. Accordingly, a correlation with the circadian cortisone output and neutrophil count has been identified.

Geographic Distribution

The geographic distribution of diseases must often be considered. It is especially obvious in infectious diseases (tropical diseases), where climatic and hygienic conditions exert influence. The physician is obliged to consider “exotic” diseases in the differential diagnosis of patients with a history of travel (tourism). In addition, even similar clinical pictures (e.g., malaria) result in a different disease course depending on the country of infection (differences in resistance).

Ethnic Groups

The patient’s ethnic background can be of importance for the diagnosis. Thalassemia occurs primarily in populations bordering the Mediterranean. Sickle cell anemia is present nearly exclusively in black populations.

Profession and Leisure

The profession of a patient can provide diagnostic clues. Occupational diseases are defined by a clear correlation between occupational activity and disease.

Besides occupational diseases, leisure pursuits are to be considered. Diseases are often observed due to sporting activities.

Precluding or Promoting Diseases

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From medical experience, certain diseases rarely occur simultaneously, whereas others are associated with each other. Patients with chronic alcohol abuse seldom develop liver cirrhosis and chronic pancreatitis at the same time. Similarly, there are practically no incidences of malaria in patients with sickle cell anemia. Diseases of one organ can be the initial manifestation of an overall dysfunctional organism or a systemic disease that endangers practically all organs. Thus upon emergence of symptoms, other possible manifestations and locations should be carefully considered.

Differential Diagnosis by Groups of Diseases

When differentiating a clinical picture, very often it is initially impossible to identify the real diagnosis, namely the nosological entity. Until relevant findings are present, one has to be content with the classification into one of the groups of diseases. In all unclear cases, consideration is almost always given to this at the beginning of the differential diagnostic process.

  • Degenerative conditions
  • Infectious disease
  • Immune mediated diseases
  • Tumors
  • Metabolic diseases
  • Dysfunction of the endocrine system
  • Mental disorders
  • Hereditary diseases
  • Allergies
  • Intoxications