JAIDS Journal of Acquired Immune Deficiency Syndromes Publish Ahead of Print DOI: 10.1097/QAI.0000000000001433
RISK OF COLORECTAL CANCER AND ASSOCIATED MORTALITY IN HIV: A SYSTEMATIC REVIEW
D
AND META-ANALYSIS
Tony ANTONIOU,3,5,6
1
EP TE
Tyler J. O’NEILL,1,2; Joseph Djiometio NGUEMO,3; Anne-Marie TYNAN,4; Ann N. BURCHELL,1,5,6;
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto,
Canada 2
Ontario HIV Treatment Network, Toronto, Canada
3
Department of Family and Community Medicine, St. Michael’s Hospital, Toronto, Canada
4
5
C
Centre for Urban Health Solutions, St. Michael’s Hospital, Toronto, Canada
Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St. Michael’s Hospital,
6
C
Toronto, Canada
A
Department of Family and Community Medicine, University of Toronto, Canada
Correspondence and Re-prints: Tony Antoniou, Ph.D.; Department of Family and Community Medicine, St. Michael’s Hospital, 410 Sherbourne Street – 4th Floor, Toronto, Ontario, Canada,
M4X 1K2; phone: 1-416-867-7460 ext. 8344; fax: 1-416-867-3726; email: [email protected]
1
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Conference Presentation: This work was presented, in part, at the Canadian Association for HIV Research (CAHR) Annual Conference, held in Winnipeg, Manitoba, Canada, May 11-15, 2016 (Abstract CSP5.13, “A Meta-Analysis of the Incidence of Colorectal Cancer in Persons with HIV”).
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Conflicts of Interest and Source of Funding: The authors have no conflict of interest to declare related to this work. No funder had any role in the study design, data analysis, decision to
publish, or preparation of the manuscript. This project is supported by funds from the Ontario
EP TE
HIV Treatment Network. Tony Antoniou is supported by a new investigator award from the Canadian Institutes of Health Research (CIHR). Tyler J. O’Neill is supported by the Ontario HIV Treatment Network and through a Canadian Observational Cohort (CANOC) Collaborative Research Centre award – a joint program of CANOC and the CIHR Canadian HIV Trials Network (CTN 242), the Ontario HIV Treatment Network, and the University of Toronto.
Disclaimer: The opinions, results, and conclusions are those of the authors and no endorsement by St. Michael’s Hospital, the University of Toronto, or the Ontario HIV Treatment Network is
C
intended or should be inferred.
C
Running Head: Colorectal Cancer in HIV Abstract word count: 209
A
Text word count: 3488
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
2
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Abstract Background: As people with HIV live longer, the numbers of colorectal cancer cases are expected to increase. We sought to compare colorectal cancer incidence and cause-specific
Design: Systematic review and meta-analysis.
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mortality among people living with and without HIV.
Methods: We searched five electronic databases to 28 June 2016 for primary studies reporting
EP TE
standardized incidence ratios (SIR), standardized mortality ratios (SMR)/hazard ratios or data sufficient for estimating these summary measures. We performed a random-effects pooled analysis to estimate SIR and SMR of colorectal cancer in HIV.
Results: Of 8,110 articles, we included 27 studies from North America (n=18), Europe (n=7), the Pacific region (n=4), and South America (n=1). Overall, 1,660 cases of colorectal cancer and colon cancer (excluding rectal cancer) occurred among 1,696,070 persons with HIV. In pooled analysis, we found no summary risk of malignancy among those with HIV relative to an uninfected population (SIR 1.00; 95% confidence interval [CI] 0.82 to 1.22; I2=89.2%). Colorectal
C
cancer-specific mortality was higher among people with HIV but did not reach statistical significance (SMR 2.09; 95% CI 1.00 to 4.40; I2=85.0%).
C
Conclusion: Rates of colorectal cancer are similar between people with and without HIV. Existing screening guidelines are likely adequate for people with HIV.
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Key words: colorectal neoplasms/epidemiology; HIV infections/complications; meta-analysis; incidence
3
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Introduction People with HIV are at higher risk of cancer than HIV-negative individuals.1-3 Although rates of classic AIDS-defining malignancies have declined since the introduction of combination antiretroviral therapy,4-6 the incidence of infection-related malignancies such as anal cancer, liver cancer and Hodgkin’s lymphoma have increased over the same period and occur at rates
D
that are markedly higher than those of the general population.1,3,7 The postulated mechanism for the heightened risk of malignancy, particularly infection-related disease, reflects a causal complement comprising risk factors such as smoking, oncogenic pathogen co-infection and HIV-
EP TE
related immunosuppression.1,8 A central role for immunosuppression is supported by results of a recent meta-analysis documenting a higher incidence of infection-related cancers in both people with HIV and organ transplant recipients relative to the general population.2 Although this same meta-analysis did not find a higher risk of non-infection associated epithelial cancers (e.g. breast, colorectal cancers) among people with HIV, the incidence of these malignancies may increase in this population by virtue of the age-related risk for these cancers and the prolonged life expectancy of people with HIV.9
Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America, with an estimated 49,190 expected to die from the disease in 201610. Early detection and
C
treatment of CRC is associated with improved prognosis and facilitated by period screening using endoscopic visualization or fecal occult blood testing11. Current guidelines recommend
C
that screening for CRC be initiated at the age of 50 years among people at average risk for disease, with earlier and more frequent screening advocated for individuals at higher risk for CRC, such as those with inflammatory bowel disease or first degree relatives with a history of
A
this illness11. Although people with HIV are generally considered at average risk for CRC, there
are inconsistent reports on the epidemiology of CRC in this population with respect to disease risk. Specifically, the standardized incidence ratio (SIR) for CRC in persons with HIV relative to the general population has ranged from 0.45 to 2.3 across studies4,12-20. Furthermore, the
prevalence of adenomatous polyps, known precursors of malignancy, among people with HIV exceed the prevalence of the general population (range 1.0 to 34.3%) in most, but not all, studies21-25. 4
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Previous meta-analyses reported SIR and 95% confidence intervals (CI) of CRC in persons with HIV of 0.97 (0.78 to 1.19) up to March 20072 and 1.1 (0.69 to 1.7) up to March 20093. However, several new studies have been published since the last review was undertaken and no reviews have examined colorectal cancer-related mortality among people with HIV7,9,26-29. Accordingly, we aimed to systematically identify observational studies, assess study quality, and estimate
D
pooled SIRs of CRC among people with HIV, compared to a referent population of persons not living with HIV. Our secondary aims were to summarize evidence for differences between
persons with and without HIV with respect to site and stage at diagnosis, treatment modalities
EP TE
and all-cause and CRC-specific mortality. These data are critical to identify whether people with HIV are at higher risk for CRC than the general population and to inform screening guidelines for these patients.
Methods
Search strategy and inclusion criteria
Our study protocol is described elsewhere (modifications in Supplementary Table 1)30. Briefly,
C
we searched five databases (Ovid MEDLINE, Ovid EMBASE, Cumulative Index of Nursing and Allied Health Literature, Scopus and Web of Science) for potentially relevant studies published
C
in English up to 28 June 2016 (Supplementary Material Table 2 for MEDLINE search strategy). The MEDLINE search strategy was adapted for the other databases searched. Iterative secondary reference searching of included publications was conducted to identify other
A
potentially relevant studies. The primary outcome of the systematic review is the SIR of CRC among people with HIV relative to HIV-negative individuals. A study was eligible for initial inclusion if it: 1) provided a comparison of the incidence of CRC (including colon or colorectal) in adults (≥18 years) with HIV and a referent population of HIV-negative individuals; 2) used an observational study design; and, 3) reported SIR and 95% CI, or sufficient information to estimate both (total number of adults with HIV, duration of follow-up, observed number of cases of CRC or colon cancer during follow-up), and corresponding data for the HIV-negative comparator population. . Secondary outcomes included site (proximal versus distal colon, colon 5
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
versus rectum) and stage of diagnosis, treatment modalities and outcomes, including standardized mortality ratio (SMR) (or equivalents, including hazard ratio (HR)) of all-cause or CRC-specific mortality among those with HIV relative to a referent HIV uninfected population (Supplementary Material Table 3). References were managed in RefWorks-COS© (Proquest LLC, Cambridge Information Group, Bethesda, USA). After de-duplication, three authors (T.J.O.,
D
J.D.N., T.A.) independently screened titles and abstracts using DistillerSR™ (Evidence Partners, Ottawa, Canada), with a fourth reviewer (A.M.T.) consulted when necessary.
EP TE
When two or more publications reported the same endpoint from one institution, cohort, or study, each article was reviewed to consider potential for pooling outcomes based on reported data. Specifically, we considered whether individual publications from the study overlapped in the source populations giving rise to cases of CRC and referent controls and the period of time during which the study was conducted. When two or more publications were identified that were deemed sufficiently alike based on these characteristics, we included only the study with the longest duration of follow-up in the meta-analysis and provided a qualitative description of the remaining studies.
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Data extraction and quality assessment
Full text articles were retrieved and three authors (T.J.O., T.A., and J.D.N.) independently abstracted study data using standardized forms. Studies were further excluded if they provided
C
insufficient data to estimate outcomes of interest. Data extracted included publication details, study design and methods, study sample/participant characteristics, and reported outcome
A
measure(s), including variables used to standardize SIR/SMR estimates (Supplementary Material Table 4). For 10% of the included studies, data were double extracted to check for accuracy. Differences in publication inclusion and data abstraction were resolved through consensus.
Two reviewers assessed the quality of included studies using the Newcastle-Ottawa Scale. This scale awards a maximum of nine stars to each study: four stars for the adequate selection of study groups, two stars for comparability of study groups on the basis of the design and analysis, and three stars for the adequate ascertainment of the outcome. Stars were awarded 6
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
based on a pre-defined list of criteria outlined in the scale. We defined studies that scored seven out of nine as high quality.31,32. Disagreement in study eligibility, data extraction, and quality assessment were resolved by consensus between reviewers. This process involved both reviewers together returning to the original abstract and/or manuscript to review study eligibility according to the protocol and re-abstract the relevant data. Finally, two team
D
members (T.J.O and T.A.) reviewed all data to ensure accuracy before analysis. Statistical analysis
EP TE
We report the SIR and 95% CI of CRC among persons with HIV relative to rates in persons not infected with HIV. If point estimates and spread or variability were not directly reported, we estimated unadjusted SIR and 95% CI using reported observed and expected cases. We assessed derived ratios of CRC and colon cancers independently and in a summary effect using the method by DerSimonian and Laird33 and assumptions of a random effects model weighted by the inverse of the variances, with ascertainment of individual study influence on summary estimates..
We used the I2 statistic to estimate the percentage of variability between studies caused by
C
between-study heterogeneity34. We defined substantial heterogeneity as I2 > 60%. We reasoned that sources of heterogeneity could be related to temporal changes in the epidemiology of cancer among people with HIV, country of publication, sources of cases and controls (e.g.
C
population-based registries versus clinical cohorts) and patient characteristics such as sex. Accordingly, a priori defined sub-group meta-analyses were conducted to explore potential
A
sources of heterogeneity based on available reported data, including sex, study location (United States vs. others), and whether the study reported data from the period before or after (1996 and onward) the introduction of combination antiretroviral therapy (cART). For outcomes with at least 10 individual studies, publication bias was assessed by constructing a funnel plot35, by Egger’s regression asymmetry test, and by Begg’s adjusted rank correlation test36. Individual study influence was assessed by removal-and-replacement of individual studies and assessment of change in summary estimates. Statistical analyses were carried out in RevMan5 (The Cochrane Collaboration, London, UK). A two-sided p value
RISK OF COLORECTAL CANCER AND ASSOCIATED MORTALITY IN HIV: A SYSTEMATIC REVIEW
D
AND META-ANALYSIS
Tony ANTONIOU,3,5,6
1
EP TE
Tyler J. O’NEILL,1,2; Joseph Djiometio NGUEMO,3; Anne-Marie TYNAN,4; Ann N. BURCHELL,1,5,6;
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto,
Canada 2
Ontario HIV Treatment Network, Toronto, Canada
3
Department of Family and Community Medicine, St. Michael’s Hospital, Toronto, Canada
4
5
C
Centre for Urban Health Solutions, St. Michael’s Hospital, Toronto, Canada
Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St. Michael’s Hospital,
6
C
Toronto, Canada
A
Department of Family and Community Medicine, University of Toronto, Canada
Correspondence and Re-prints: Tony Antoniou, Ph.D.; Department of Family and Community Medicine, St. Michael’s Hospital, 410 Sherbourne Street – 4th Floor, Toronto, Ontario, Canada,
M4X 1K2; phone: 1-416-867-7460 ext. 8344; fax: 1-416-867-3726; email: [email protected]
1
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Conference Presentation: This work was presented, in part, at the Canadian Association for HIV Research (CAHR) Annual Conference, held in Winnipeg, Manitoba, Canada, May 11-15, 2016 (Abstract CSP5.13, “A Meta-Analysis of the Incidence of Colorectal Cancer in Persons with HIV”).
D
Conflicts of Interest and Source of Funding: The authors have no conflict of interest to declare related to this work. No funder had any role in the study design, data analysis, decision to
publish, or preparation of the manuscript. This project is supported by funds from the Ontario
EP TE
HIV Treatment Network. Tony Antoniou is supported by a new investigator award from the Canadian Institutes of Health Research (CIHR). Tyler J. O’Neill is supported by the Ontario HIV Treatment Network and through a Canadian Observational Cohort (CANOC) Collaborative Research Centre award – a joint program of CANOC and the CIHR Canadian HIV Trials Network (CTN 242), the Ontario HIV Treatment Network, and the University of Toronto.
Disclaimer: The opinions, results, and conclusions are those of the authors and no endorsement by St. Michael’s Hospital, the University of Toronto, or the Ontario HIV Treatment Network is
C
intended or should be inferred.
C
Running Head: Colorectal Cancer in HIV Abstract word count: 209
A
Text word count: 3488
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
2
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Abstract Background: As people with HIV live longer, the numbers of colorectal cancer cases are expected to increase. We sought to compare colorectal cancer incidence and cause-specific
Design: Systematic review and meta-analysis.
D
mortality among people living with and without HIV.
Methods: We searched five electronic databases to 28 June 2016 for primary studies reporting
EP TE
standardized incidence ratios (SIR), standardized mortality ratios (SMR)/hazard ratios or data sufficient for estimating these summary measures. We performed a random-effects pooled analysis to estimate SIR and SMR of colorectal cancer in HIV.
Results: Of 8,110 articles, we included 27 studies from North America (n=18), Europe (n=7), the Pacific region (n=4), and South America (n=1). Overall, 1,660 cases of colorectal cancer and colon cancer (excluding rectal cancer) occurred among 1,696,070 persons with HIV. In pooled analysis, we found no summary risk of malignancy among those with HIV relative to an uninfected population (SIR 1.00; 95% confidence interval [CI] 0.82 to 1.22; I2=89.2%). Colorectal
C
cancer-specific mortality was higher among people with HIV but did not reach statistical significance (SMR 2.09; 95% CI 1.00 to 4.40; I2=85.0%).
C
Conclusion: Rates of colorectal cancer are similar between people with and without HIV. Existing screening guidelines are likely adequate for people with HIV.
A
Key words: colorectal neoplasms/epidemiology; HIV infections/complications; meta-analysis; incidence
3
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Introduction People with HIV are at higher risk of cancer than HIV-negative individuals.1-3 Although rates of classic AIDS-defining malignancies have declined since the introduction of combination antiretroviral therapy,4-6 the incidence of infection-related malignancies such as anal cancer, liver cancer and Hodgkin’s lymphoma have increased over the same period and occur at rates
D
that are markedly higher than those of the general population.1,3,7 The postulated mechanism for the heightened risk of malignancy, particularly infection-related disease, reflects a causal complement comprising risk factors such as smoking, oncogenic pathogen co-infection and HIV-
EP TE
related immunosuppression.1,8 A central role for immunosuppression is supported by results of a recent meta-analysis documenting a higher incidence of infection-related cancers in both people with HIV and organ transplant recipients relative to the general population.2 Although this same meta-analysis did not find a higher risk of non-infection associated epithelial cancers (e.g. breast, colorectal cancers) among people with HIV, the incidence of these malignancies may increase in this population by virtue of the age-related risk for these cancers and the prolonged life expectancy of people with HIV.9
Colorectal cancer (CRC) is the third leading cause of cancer-related death in North America, with an estimated 49,190 expected to die from the disease in 201610. Early detection and
C
treatment of CRC is associated with improved prognosis and facilitated by period screening using endoscopic visualization or fecal occult blood testing11. Current guidelines recommend
C
that screening for CRC be initiated at the age of 50 years among people at average risk for disease, with earlier and more frequent screening advocated for individuals at higher risk for CRC, such as those with inflammatory bowel disease or first degree relatives with a history of
A
this illness11. Although people with HIV are generally considered at average risk for CRC, there
are inconsistent reports on the epidemiology of CRC in this population with respect to disease risk. Specifically, the standardized incidence ratio (SIR) for CRC in persons with HIV relative to the general population has ranged from 0.45 to 2.3 across studies4,12-20. Furthermore, the
prevalence of adenomatous polyps, known precursors of malignancy, among people with HIV exceed the prevalence of the general population (range 1.0 to 34.3%) in most, but not all, studies21-25. 4
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
Previous meta-analyses reported SIR and 95% confidence intervals (CI) of CRC in persons with HIV of 0.97 (0.78 to 1.19) up to March 20072 and 1.1 (0.69 to 1.7) up to March 20093. However, several new studies have been published since the last review was undertaken and no reviews have examined colorectal cancer-related mortality among people with HIV7,9,26-29. Accordingly, we aimed to systematically identify observational studies, assess study quality, and estimate
D
pooled SIRs of CRC among people with HIV, compared to a referent population of persons not living with HIV. Our secondary aims were to summarize evidence for differences between
persons with and without HIV with respect to site and stage at diagnosis, treatment modalities
EP TE
and all-cause and CRC-specific mortality. These data are critical to identify whether people with HIV are at higher risk for CRC than the general population and to inform screening guidelines for these patients.
Methods
Search strategy and inclusion criteria
Our study protocol is described elsewhere (modifications in Supplementary Table 1)30. Briefly,
C
we searched five databases (Ovid MEDLINE, Ovid EMBASE, Cumulative Index of Nursing and Allied Health Literature, Scopus and Web of Science) for potentially relevant studies published
C
in English up to 28 June 2016 (Supplementary Material Table 2 for MEDLINE search strategy). The MEDLINE search strategy was adapted for the other databases searched. Iterative secondary reference searching of included publications was conducted to identify other
A
potentially relevant studies. The primary outcome of the systematic review is the SIR of CRC among people with HIV relative to HIV-negative individuals. A study was eligible for initial inclusion if it: 1) provided a comparison of the incidence of CRC (including colon or colorectal) in adults (≥18 years) with HIV and a referent population of HIV-negative individuals; 2) used an observational study design; and, 3) reported SIR and 95% CI, or sufficient information to estimate both (total number of adults with HIV, duration of follow-up, observed number of cases of CRC or colon cancer during follow-up), and corresponding data for the HIV-negative comparator population. . Secondary outcomes included site (proximal versus distal colon, colon 5
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
versus rectum) and stage of diagnosis, treatment modalities and outcomes, including standardized mortality ratio (SMR) (or equivalents, including hazard ratio (HR)) of all-cause or CRC-specific mortality among those with HIV relative to a referent HIV uninfected population (Supplementary Material Table 3). References were managed in RefWorks-COS© (Proquest LLC, Cambridge Information Group, Bethesda, USA). After de-duplication, three authors (T.J.O.,
D
J.D.N., T.A.) independently screened titles and abstracts using DistillerSR™ (Evidence Partners, Ottawa, Canada), with a fourth reviewer (A.M.T.) consulted when necessary.
EP TE
When two or more publications reported the same endpoint from one institution, cohort, or study, each article was reviewed to consider potential for pooling outcomes based on reported data. Specifically, we considered whether individual publications from the study overlapped in the source populations giving rise to cases of CRC and referent controls and the period of time during which the study was conducted. When two or more publications were identified that were deemed sufficiently alike based on these characteristics, we included only the study with the longest duration of follow-up in the meta-analysis and provided a qualitative description of the remaining studies.
C
Data extraction and quality assessment
Full text articles were retrieved and three authors (T.J.O., T.A., and J.D.N.) independently abstracted study data using standardized forms. Studies were further excluded if they provided
C
insufficient data to estimate outcomes of interest. Data extracted included publication details, study design and methods, study sample/participant characteristics, and reported outcome
A
measure(s), including variables used to standardize SIR/SMR estimates (Supplementary Material Table 4). For 10% of the included studies, data were double extracted to check for accuracy. Differences in publication inclusion and data abstraction were resolved through consensus.
Two reviewers assessed the quality of included studies using the Newcastle-Ottawa Scale. This scale awards a maximum of nine stars to each study: four stars for the adequate selection of study groups, two stars for comparability of study groups on the basis of the design and analysis, and three stars for the adequate ascertainment of the outcome. Stars were awarded 6
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
based on a pre-defined list of criteria outlined in the scale. We defined studies that scored seven out of nine as high quality.31,32. Disagreement in study eligibility, data extraction, and quality assessment were resolved by consensus between reviewers. This process involved both reviewers together returning to the original abstract and/or manuscript to review study eligibility according to the protocol and re-abstract the relevant data. Finally, two team
D
members (T.J.O and T.A.) reviewed all data to ensure accuracy before analysis. Statistical analysis
EP TE
We report the SIR and 95% CI of CRC among persons with HIV relative to rates in persons not infected with HIV. If point estimates and spread or variability were not directly reported, we estimated unadjusted SIR and 95% CI using reported observed and expected cases. We assessed derived ratios of CRC and colon cancers independently and in a summary effect using the method by DerSimonian and Laird33 and assumptions of a random effects model weighted by the inverse of the variances, with ascertainment of individual study influence on summary estimates..
We used the I2 statistic to estimate the percentage of variability between studies caused by
C
between-study heterogeneity34. We defined substantial heterogeneity as I2 > 60%. We reasoned that sources of heterogeneity could be related to temporal changes in the epidemiology of cancer among people with HIV, country of publication, sources of cases and controls (e.g.
C
population-based registries versus clinical cohorts) and patient characteristics such as sex. Accordingly, a priori defined sub-group meta-analyses were conducted to explore potential
A
sources of heterogeneity based on available reported data, including sex, study location (United States vs. others), and whether the study reported data from the period before or after (1996 and onward) the introduction of combination antiretroviral therapy (cART). For outcomes with at least 10 individual studies, publication bias was assessed by constructing a funnel plot35, by Egger’s regression asymmetry test, and by Begg’s adjusted rank correlation test36. Individual study influence was assessed by removal-and-replacement of individual studies and assessment of change in summary estimates. Statistical analyses were carried out in RevMan5 (The Cochrane Collaboration, London, UK). A two-sided p value
