How to conduct meta-analysis: A Basic Tutorial Arindam Basu University of Canterbury May 12, 2017 Concepts of meta-analyses Meta analysis refers to a process of integration of the results of many studies to arrive at evidence syn- thesis (Normand, 1999). Meta analysis is essentially systematic review; however, in addition to narrative summary that is conducted in systematic review, in meta analysis, the analysts also numerically pool the results of the studies and arrive at a summary estimate. In this paper, we discuss the key steps of conducting a meta analysis. We intend to discuss the steps of a simple meta analysis with a demonstration of the key steps from a published paper on meta analysis and systematic review of the effectiveness of salt restricted diet on blood pressure control. This paper is a basic introduction to the process of meta-analysis. In subse- quent papers in this series, we will discuss how you can conduct meta analysis of diagnostic and screening studies, and principles of network meta analyses, where you can conduct a meta analysis with more than one intervention or exposure variable. Nine Steps to Meta Analyses We recommend in general the following nine steps of meta analysis. These nine steps are in general applicable to all meta-analyses. 1. Frame a question (based on a theory) 2. Run a search (on Pubmed/Medline, Google Scholar, other sources) 3. Read the abstract and title of the individual papers. 4. Abstract information from the selected set of final articles. 5. Determine the quality of the information in these articles. This is done using a judgment of their internal validity but also using the GRADE criteria 6. Determine the extent to which these articles are heterogeneous 7. Estimate the summary effect size in the form of Odds Ratio and using both fixed and random effects models and construct a forest plot 8. Determine the extent to which these articles have publication bias and run a funnel plot 9. Conduct subgroup analyses and meta regression to test if there are subsets of research that capture the summary effects Step I: Frame a Question For framing an answerable question in a meta analysis, use the PICO framework (Schardt et al., 2007). PICO is an acronym for "Participant-Intervention-Comparator-Outcomes". \Participant" here refers to 1 PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017 individuals or population of interest to us. For example, if we are interested in the effectiveness of a drug such as nedocromil on bronchoconstriction (narrowing of air passages) among adult asthma patients, then we shall include only adult asthmatics for our study, not children or older adults (if such individuals are not of our interest); on the other hand, if we are interested to study the effectiveness of mindfulness meditation for anxiety for adults, then again adult age group would be our interest; we could further narrow down the age band to our interest. Intervention needs to be as broadly or as narrowly defined keeping only the interventions of our interest. Usually, meta-analyses are done in assimilating studies that are RCTs or quasi-experimental studies where pairs of interventions (intervention versus placebo or interventions versus conventional treatment or inter- ventions and no treatment) are compared (Normand, 1999). Note that meta-analyses are not necessarily restricted only to randomised controlled trials, these are now increasingly applied to observational study de- signs as well for example cohort and case control studies; in these situations, we refer to the specific expsoure variables of our interest (Stroup et al., 2000). Meta-analyses are also conducted for diagnostic and screening studies (Hasselblad and Hedges, 1995) Let's say we are interested to test the hypothesis that consumption of plant-based diets is associated with reduced risk of cardiovascular illnesses. You can see that for ethical reasons, it is not possible to conduct randomised controlled trials so that one group will be forced to consume plant based diet and the other group will be forced to consume non-plant based diet, but it is possible to obtain that information about heart diseases from two groups of people who have consumed and not consumed certain levels of vegetarian items in their diets. Such studies are observational epidemiological studies and using observational studies such as cohort and case control studies. In such situations, it is useful to summarise findings of cohort and case control studies. Intervention then is not appropriate; however, we use the term "Exposure". Likewise, the comparison group is important as well. The comparison group can be "no intervention", or "placebo", or "usual treatment". The outcomes that we are interested can be narrowly or broadly defined based on the objective of the meta analysis. If the outcome is narrowly defined, then the meta analysis is only restricted to that outcome, for instance, if we are interested to study the effectiveness of mindfulness meditation on anxiety then, anxiety is our outcome; we are not interested to find out if mindfulness is effective for depression. On the other hand, if the objective of hte study is to test if mindfulness meditation is useful for "any health outcome", then the scope of the search is much wider. So, after you have set up your theory and your question, now is the time to rewrite the question and reframe it as a PICO formatted question. Say we are interested to find out if minduflness meditation is effective for anxiety, then we may state the question in PICO as follows: • P: Adults (age 18 years and above), both sexes, all ethnicity, all nationality • I: Mindfulness Meditation • C: Placebo, Or No Intervention, or Anxiolytics Or Traditional Approaches, or Drug Based Approaches, or Other Cognitive Behavioural Therapy • O: Anxiety Symptom Scores, or Generalised Anxiety Then, on the basis of PICO, we reframe the question as follows: "Among Adults, compared with all other approaches, what is the effectiveness of Mindfulness Meditation for the relief of Anxiety?" Step II: Conduct a Search of the Literature Databases After you have decided the PICO, you will conduct a search of the literature databases. This will help you to identify the appropriate search terms. These search terms are arranged using Boolean Logic, fuzzy logic, specific search related controlled vocabulary, symbols of truncation or expansion, and placement of the terms in different sections of a reported study (Tuttle et al., 2009). In Boolean Logic, you use the connectors, 2 PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017 "AND", "OR", and "NOT" in various combinations to expand or narrow down search results and findings. For example, • "Adults" AND "Mindfulness Meditation" will find only those articles that have BOTH adults AND mindfulness meditation as their subject topics. While, • "Adults" OR "Mindfulness Meditation" will find all articles that have EITHER "Adults" OR "Mind- fulness Meditation" in their subject topics, so the number of results returned will be larger. • "Adults" NOT "Mindfulness Meditation" will find only those articles that contain "Adults" but will exclude all articles that have "Mindfulness Meditation" as their topic area. In addition to the use of Boolean logic, you can also use "fuzzy logic" to search for specific articles. When you use fuzzy logic, you use search terms where you use words like "Adults" NEAR "Mindfulness" or "Adults" WITHIN 5 Words of "Mindfulness" to search for articles that are very specific. These can be combined in many different ways. Many databases, such as Pubmed/Medline, contain MeSH (Medical Subject Headings) as controlled vo- cabulary where hte curators of thse databses maintain or archive difernet articles under specific search terms (Robinson and Dickersin, 2002). When you search Medline or Pubmed, you can use MeSH terms to search for your studies. You can use or combine MeSH terms along with other terms to search more widely or more comprehensively. Besides these, you will use specific symbols such as asterisk (*) marks and dollar signs to indicate truncation or find related terms to find out articles. For example, if you use something like "Meditat$" in a search term, then you can find articles that use the terms "meditating", or "meditation", or "meditative" or "Meditational"; you will find list of such symbols in the documentation section of the database that you intend to search (Robinson and Dickersin, 2002). Finally, search terms can occur in many different sections and parts of a study report. One way to search is to search the title and abstract of most studies. Another way to search place to search is within the entire body of the article. Thus, combining these various strategies, you can run a comprehensive search of the publications or research that will contain data that you can use for your meta-analysis. Step III: Select the articles for meta analysis by reading Titles and Abstracts and full texts First, read the titles and abstracts of all relevant searched papers. But before you do so, set up a scheme where you will decide that you will select and reject articles for your meta analysis. For example, you can set up a scheme where you can write: • The article is irrelevant for the study question • The article does not have the relevant population • The article does not have the relevant intervention (or exposure) • The article does not have a relevant comparison group • The article does not discuss the outcome that is of interest to this research • The article is published in a non-standard format and not suitable for review • The article is published in a foreign language and cannot be translated • The article is published outside of the date ranges • The article is a duplicate of another article (same publication published twice) 3 PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017 Use this scheme to go through each and every article you retrieved initially on the basis of reading their titles and abstracts.