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Systematic Review Of Observational Studies By Yusuf Abdu Misau


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Systematic Review Of Observational Studies By Yusuf Abdu Misau

  1. 1. Matrix  of Delayed Test & Presentation among Antiretroviral Naïve HIV Patients (Systematic Review and Meta-Analysis of Observational Studies )   Yusuf Abdu Misau  (PhD Candidate MHA090018 ) Dept of social and preventive medicine University of Malaya    
  2. 2. Supervisors: <ul><li>Asso Prof Nabilla Al-Sadat </li></ul><ul><li>Family Health Unit, Dept of SPM, </li></ul><ul><li>Faculti perubatan, Universiti Malaya, Malaysia </li></ul><ul><li>  </li></ul><ul><li>Dr Sajaratulnisah Othman </li></ul><ul><li>Dept of Primary care Medicine </li></ul><ul><li>aculti perubatan, Universiti Malaya, Malaysia </li></ul>
  3. 3. The Candidate <ul><li>Dr Yusuf Abdu Misau </li></ul><ul><li>Born 1975, Nigeria </li></ul><ul><li>MBBS-2004 ABU Zaria-Nigeria </li></ul><ul><li>Medical officer 2005-2006 </li></ul><ul><li>Medical Registrar, ABUTH Zaria 2006 </li></ul><ul><li>MPH-2009 UM, Malaysia </li></ul><ul><li>PhD Candidate 2009 UM, Malaysia </li></ul>
  4. 4. Research works <ul><li>Major works: </li></ul><ul><li>Antibiotic for chronic AIDS Diarrhea in adults-Protocol stage, Cochrane database of systematic review </li></ul><ul><li>Depression among Newly diagnosed HIV patients in Nigeria, CSS, (ongoing) </li></ul><ul><li>KAP Hand-washing among health care workers in Bauchi specialist hospital, Nig (ongoing) </li></ul>
  5. 5. contents <ul><li>Title </li></ul><ul><li>Statement of problem </li></ul><ul><li>Objectives </li></ul><ul><li>Study design </li></ul><ul><li>Public health significance </li></ul><ul><li>Methodology </li></ul><ul><li>Source of funding </li></ul><ul><li>Time-line </li></ul>
  6. 6. Title <ul><li>Matrix  of Delayed Test & Presentation among Antiretroviral Naïve HIV Patients </li></ul><ul><li>Systematic Review and Meta-Analysis of Observational Studies </li></ul>
  7. 7. Statement of problem <ul><li>HIV first diagnosed in 1981 </li></ul><ul><li>Antiretroviral treatment first used in 1987 </li></ul><ul><li>Antiretroviral treatment now over 20 years old </li></ul><ul><li>HIV death still remain HIGH: 2million death in 2007 alone </li></ul><ul><li>29 million death since 1981 </li></ul><ul><li>2.7 million new infection in 2007 alone </li></ul>
  8. 8. Statement of problem <ul><li>Major preventable causes of death: </li></ul><ul><ul><li>Lack of access to antiretroviral drugs </li></ul></ul><ul><ul><li>Late presentation for test and care </li></ul></ul>
  9. 9. Late presentation: definitions <ul><li>European definition: </li></ul><ul><li>Late presentation is defined as persons presenting for care with a CD4 count below 350 cells/µL or presenting with an AIDS defining event. </li></ul><ul><li>Presentation with advanced HIV disease: is defined as persons fulfilling the above definition except that the CD4 threshold is below 200 cells/µL as opposed to below 350 cells/µL. That is, this group will still be classified as late presenters, but categorized according to their lower CD4 count. </li></ul>
  10. 10. Late presentation: definition <ul><li>Other definitions in literature: </li></ul><ul><li>Presence of HIV related symptoms at time of diagnosis or AIDS defining features. </li></ul><ul><li>NB: Caution is needed in Patients presenting with lymphocytes suppressing conditions; pregnancy, cytotoxics, concurrent viral infection, these conditions affects CD4 count. </li></ul>
  11. 11. Late presentation: Magnitude <ul><li>Delay in testing and presentation for care is seen worldwide, across all races, beliefs, cultures, educational backgrounds, and income class. </li></ul><ul><li>In Europe, </li></ul>
  12. 12. Objectives of this study <ul><li>The objective of this study is to assess causes and effects associated with late presentation for diagnosis and care among antiretroviral naive HIV patients. </li></ul>
  13. 13. Research questions <ul><li>What are the rates of late presentation among newly diagnosed HIV patients? </li></ul><ul><li>Why the patients do presents late? </li></ul><ul><li>Is there anything special that makes these patients presents late? </li></ul><ul><li>What are the characteristics of these late presenters? </li></ul><ul><li>What are the effects of late presentation </li></ul><ul><li>What effort has been made to address the issue of late presentation among newly diagnosed HIV patients? </li></ul>
  14. 14. The study design <ul><li>Systematic review </li></ul><ul><li>Meta-analysis </li></ul><ul><li>Systematic review and meta-analysis of observational studies </li></ul><ul><li>Bayesian Meta-analysis? </li></ul>
  15. 15. Ranking of evidence
  16. 16. Meta-analysis Of Observational Study in Epidemiology [MOOSE] <ul><li>MA has applied has been routinely done with RCT </li></ul><ul><li>But in Many situations RCT is not feasible, and only data from OS is available </li></ul><ul><li>OS are Case report, Case control, Cross sectional or Cohort studies </li></ul><ul><li>OS are prone to bias and errors </li></ul>
  17. 17. Meta-analysis Of Observational Study in Epidemiology [MOOSE] <ul><li>However MOOSE are more common than expected today </li></ul><ul><li>Between 1955-1992 there were only 678 published MOOSE </li></ul><ul><li>But 1992-1995, 525 MOOSE were published </li></ul><ul><li>In 1996 alone, 400 MOOSE were published </li></ul><ul><li>Now there is only a slight diff in number of published MOOSE and RCT in lit </li></ul>
  18. 18. Methodological issues in MOOSE <ul><li>Many standard guidelines and checklist are developed to address methodological issues </li></ul><ul><li>Eg MOOSE reporting guidelines by the MOOSE Group Atlanta 1997 </li></ul><ul><li>The Newcastle Ottawa Score for assessing nonrandomized studies </li></ul><ul><li>The CASP checklist </li></ul><ul><li>etc </li></ul>
  19. 19. Public health benefit of SR and MA <ul><li>Objective analysis and summary of data that can be translated into practice and policy </li></ul><ul><li>Establish what is known prior to further research </li></ul><ul><li>Resolve conflicting reports </li></ul><ul><li>Clarify strengths and weaknesses of studies </li></ul><ul><li>Evaluate public health programs </li></ul>
  20. 20. Public health significance of this study <ul><li>In order to understand the overall causes of delay in presentation among antiretroviral naive HIV patients, there is need for a systematic review and meta-analysis designed to synthesize the evidence based on rigorous predetermined criteria. </li></ul><ul><li>Identification and subsequent prevention of factors responsible for late presentation of HIV patients for care will improve not only the prognosis of the disease in the patients but also be of benefit to the community. The followings are some rationale for the conduction of this study: </li></ul>
  21. 21. Public health significance of this study <ul><li>improving the mortality and disability adjusted life years among antiretroviral naive HIV positive persons </li></ul><ul><li>Better and beneficial use of highly expensive anti-retroviral drugs </li></ul><ul><li>Lesser burden on health care workers and facilities, as well as improving the morale and attitude of the health care workers towards antiretroviral naive HIV positive persons </li></ul><ul><li>Enabling antiretroviral naive HIV positive persons live a productive life, contributing to the national work force and cater for their families </li></ul>
  22. 22. Public health significance of this study <ul><li>Helps reduce stigma </li></ul><ul><li>Improves prevention of the spread of HIV </li></ul><ul><li>Reduce anxiety among antiretroviral naive HIV positive persons and their family members. </li></ul><ul><li>Enables better opportunity to study individuals with HIV </li></ul><ul><li>Reduce fear of HIV/AIDS in the society </li></ul><ul><li>Enables direct involvement of antiretroviral naive HIV positive persons in the plan, design and implementation of prevention programs. </li></ul>
  23. 23. Methodology <ul><li>Design : SR and MA of observational studies </li></ul><ul><li>Types of studies </li></ul><ul><li>This review will include only observational epidemiological studies; either case-control, cross-sectional or cohort conducted among newly diagnosed HIV infected adults. Experimental studies will not have been feasible for this topic. </li></ul>
  24. 24. Types of participants <ul><li>Inclusion criteria(CASE DEFINITION): </li></ul><ul><li>Adults (18 years and above), both sexes, newly diagnosed with HIV infection </li></ul><ul><li>NO prior use of antiretroviral drugs </li></ul>
  25. 25. Types of exposure <ul><li>HIV positive status </li></ul><ul><li>Risk Perception of HIV infection as well as availability of test and treatment </li></ul><ul><li>Socio-demographic characteristics </li></ul>
  26. 26. Types of outcome measures <ul><li>Primary outcomes: </li></ul><ul><li>Late presentation: defined as presence of HIV associated symptoms at the time of diagnosis or presentation: opportunistic infections or AIDS defining features at the time of diagnosis or presentation for care. </li></ul><ul><li>  </li></ul>
  27. 27. Types of outcome measures <ul><li>Secondary outcomes : </li></ul><ul><li>Time to presentation after positive diagnosis: This will be defined as time taken to present for definitive care after being diagnosed HIV positive </li></ul><ul><li>Death due to late presentation </li></ul><ul><li>Changes in CD4 Count after commencement of HAART </li></ul><ul><li>Adverse events: </li></ul><ul><li>Classified as: </li></ul><ul><li>Severe opportunistic infections leading to hospitalizations </li></ul><ul><li>Failure or resistance to antiretroviral therapy </li></ul>
  28. 28. Electronic searches <ul><li>An exhaustive electronic search for all relevant studies both published and unpublished will be conducted. No languages restrictions will be used. The following major databases will be searched using search terms and strategies below: </li></ul><ul><li>MEDLINE (1966-Date) </li></ul><ul><li>EMBASE (1974-Date) </li></ul><ul><li>AIDSsearch (1980-Date) </li></ul><ul><li>LILACS (1980-Date) </li></ul><ul><li>Cochrane (1993-Date) </li></ul>
  29. 29. Specific Search terms <ul><li>Acquired Immunodeficiency Syndrome, Human immunodeficiency virus, AIDS/HIV, immunocompromised, advanced immunocompromised, advanced Immuno-suppressed, Immuno-suppressed, advanced Immuno-suppression, Immuno-suppression, Advanced HIV, Low CD4, Delayed presentation, Delayed diagnosis, Late presentation, Late presenters, Late diagnosis, late test, </li></ul>
  30. 30. Specific Search terms <ul><li>Late diagnosis, Cohort studies, Case-control studies, Case-case comparison, Cross-sectional study, descriptive study, descriptive survey, Survey, Factors, determinants, Risk factors, Consequences, Care, Treatment, Risk, Mortality, Antiretroviral therapy, Highly active antiretroviral therapy, HAART, Management, Infection, </li></ul>
  31. 31. Searching other sources <ul><li>Conference Proceedings </li></ul><ul><li>International conference on opportunistic pathogens </li></ul><ul><li>International AIDS Conference </li></ul><ul><li>Conference on Retroviruses and Opportunistic Infections </li></ul><ul><li>The British HIV Association conference </li></ul><ul><li>International Congress on Drug Therapy in HIV Infection </li></ul><ul><li>National summit on HIV diagnosis </li></ul><ul><li>Annual Conference on retroviruses and opportunistic infections </li></ul><ul><li>International AIDS society conference on HIV pathogenesis, treatments and care </li></ul>
  32. 32. Searching other sources <ul><li>Writing to Experts </li></ul><ul><li>Contacts will be made with principal investigators of identified relevant studies if they know of other existing relevant studies. Contacts with experts were shown to be good source for obtaining relevant studies, though could be unfruitful as well. Contacts will also be made with relevant organizations such as the WHO and PEFPAR </li></ul><ul><li>Snowballing </li></ul><ul><li>Reference lists of identified studies will be eyeballed for relevant studies missed during major search. Hand-search for such studies if any will then be conducted. Articles that cited identified relevant studies will also be cross checked to retrieve and examine if they meet this review’s inclusion criteria. </li></ul><ul><li>Free Hand-search </li></ul><ul><li>Free hand-searching will be conducted for studies in un-indexed or very recent journals and conference Proceedings in local libraries such as University of Malaya Main Library and University of Malaya medical library. Contacts will be made with Authors and Editors to retrieve unpublished studies if any. </li></ul><ul><li>Ongoing studies </li></ul><ul><li>Search for ongoing studies will be conducted in the relevant registries. </li></ul>
  33. 33. Data collection and analysis <ul><li>Selection of studies </li></ul><ul><li>Data extraction and management </li></ul><ul><li>Assessment of risk of bias in included studies </li></ul><ul><li>Both the researcher and an assistant will use the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses to determine the eligibility for inclusion or exclusion from this review. The Newcastle-Ottawa Scale (NOS) is quality assessment tool developed jointly by the Universities of Newcastle, Australia and Ottawa, Canada. It is used to assess the quality of nonrandomized studies based on 'star system'. </li></ul>
  34. 34. Measures of effect of exposures <ul><li>Risk ratio (RR) will be used to express results of dichotomous outcomes with 95% confidence intervals (CI). Outcomes on continuous scales of measurement will be expressed using mean difference (MD) and standardized mean difference (SMD) if different scales have been used. </li></ul>
  35. 35. Dealing with missing data <ul><li>Where some data are missing, attempt will be made to contact authors of the primary studies for the missing data. If there is no response or there is response but could not provide data, such outcomes will be excluded from analysis. Studies with missing outcomes will be described in characteristics of studies table. </li></ul>
  36. 36. Assessment of reporting biases <ul><li>Attempt will be made to detect and if present adjust for publication bias. Publication bias is the tendency for publication of studies that show a positive result in preference to one that show a negative result.(Anders Pape Møller and Michael D. Jennions 2001) </li></ul>
  37. 37. Assessment of reporting biases <ul><li>A funnel plot will be used to assess publication bias. Asymmetry in the funnel plot of the standard error plotted against the risk ratio measured on a logarithmic scale for primary outcomes may indicate publication bias, poor methodological quality or heterogeneity. If there is no publication bias, a symmetrical funnel shaped plot is seen. </li></ul>
  38. 38. Funnel Plot in Presence of Bias <ul><li>When the true outcome effect is modest: </li></ul><ul><li>Small studies are likely to find small, non-significant effects, and are therefore less likely to be published. </li></ul><ul><li>Only small studies that by chance find a large effect size may be statistically significant and are more likely to be published. </li></ul><ul><li>Consequently, there will be a lack of small studies with small effect estimates in the funnel plot, and the plot will be skewed. </li></ul>
  39. 39. An Asymmetric Funnel Plot (indicative of publication bias) (Region of missing studies) Log Odds Ratio -2 -1 0 1 2 Precision
  40. 40. Funnel Plot Showing No Publication Bias
  41. 41. Data analysis <ul><li>Review Manager 5 and STATA will be used to analyzed the extracted data. The data will be entered by the researcher and cross checked by an assistant for accuracy. All results will be presented with 95% confidence intervals. </li></ul>
  42. 42. Subgroup analysis and investigation of heterogeneity <ul><li>Heterogeneity will be assessed in three ways: </li></ul><ul><ul><li>Graphically by using forest plot </li></ul></ul><ul><ul><li>Performing the Cochran chi-squared test and interpreted relative to degree of freedom and P value of 0.10 to determine statistical significance </li></ul></ul><ul><ul><li>I 2 test : If I 2 test value is found to be greater than 50%, it will be considered as substantial heterogeneity. </li></ul></ul>
  43. 43. Subgroup analysis and investigation of heterogeneity <ul><li>If a low level - moderate heterogeneity less than 50% is found, the random effect model will be used to adjust. If there is significant statistical heterogeneity, the possible sources of heterogeneity will be explored by removing studies with low methodological quality and by using subgroup analyses for specific outcomes. </li></ul>
  44. 44. Subgroup analysis and investigation of heterogeneity
  45. 46. Sensitivity analysis <ul><li>If there are no contraindications to combining the systematically reviewed studies, sensitivity analyses will be done to assess the robustness of the meta-analysis. </li></ul><ul><li>Sensitivity analysis is one of the criteria for ensuring sound methodological quality of meta-analysis. </li></ul>
  46. 47. Sensitivity Analysis <ul><li>Several features of the meta-analysis can be altered to gauge the robustness of the results: </li></ul><ul><ul><li>Modifying the inclusion criteria </li></ul></ul><ul><ul><li>Including and excluding questionable studies </li></ul></ul><ul><ul><li>Including and excluding unpublished studies </li></ul></ul><ul><ul><li>Weighting the analysis by study quality </li></ul></ul><ul><ul><li>Trying different ways to impute missing data </li></ul></ul><ul><ul><li>Removing each study, one by one, to see the change </li></ul></ul>
  47. 48. Issues in Systematic Reviews <ul><li>Selection bias: </li></ul><ul><ul><li>Strict adherence to protocol. </li></ul></ul><ul><li>In the discussion, some studies may be “explained away” while others are emphasized: </li></ul><ul><ul><li>Balanced view </li></ul></ul><ul><li>Rather than providing a balanced review, it is possible for a supposedly “systematic” review to provide a forum for presenting an opinion. </li></ul><ul><li>Meta-analyses, with standardized methods, give more protection against personal bias. </li></ul>
  48. 49. Issues in meta analysis <ul><li>Choosing a model </li></ul><ul><ul><li>Fixed effects model or random effects? </li></ul></ul><ul><li>Bias in meta analysis </li></ul><ul><ul><li>poor quality of studies( NOS assessment) </li></ul></ul><ul><ul><li>publication bias </li></ul></ul><ul><li>Quality control in meta analysis </li></ul><ul><ul><li>MOOSE guidelines </li></ul></ul><ul><li>Statistical Software for meta analysis </li></ul>
  49. 50. Sources of funding <ul><li>Systematic reviews and meta-analysis are relatively “cheaper” than other studies </li></ul><ul><li>Funding may be desired for relevant software, internet access, journal subscription, workshops </li></ul><ul><li>For this study, only the last two may be necessary: journal subscription and workshop </li></ul>
  50. 51. Sources of funding <ul><li>Target subscribed journals for this review are 30 at cost of 15USD per journal(1530RM) </li></ul>
  51. 52. Time line <ul><li>This study is design to be completed in 4 semesters(minimum period allowed for PhD program by UM) </li></ul><ul><li>Gantt chart (attached) shows the study flow </li></ul>
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  55. 56. Terima Kasih <ul><li>Thank you for your attention </li></ul>