Based on the provided AMSTAR assessment of a systematic literature review, the study appears to be of moderate to high quality. It fulfills several critical criteria for a systematic review, including having a clear research question, explicit inclusion criteria, and the application of the PICO framework. Moreover, the review has followed established methods, used comprehensive literature search strategies, and applied satisfactory techniques for assessing the risk of bias (RoB) in individual studies.

The use of the Newcastle-Ottawa Scale (NOS) to assess RoB further strengthens the credibility of the study. Additionally, the authors have performed an appropriate method for the statistical combination of results in meta-analysis, adequately addressed the potential impact of RoB on meta-analysis results, and accounted for RoB when interpreting the review results. Lastly, the potential sources of conflict of interest were reported, which increases the transparency of the review.

However, certain limitations in the study have been identified. For example, the authors did not fully justify their selection of study designs, did not perform data extraction in duplicate, did not provide a list of excluded studies or justify their exclusions, and did not report on the sources of funding for the studies included in the review. While the authors used funnel plots to investigate publication bias, they did not explicitly discuss its potential impact on their findings. These limitations suggest that there might be areas for improvement in the methodological rigor of this systematic review. Despite these limitations, the study is overall reasonably well-conducted and provides valuable information.

Assessment of methodological quality using Amstar 2.0

Domain	Assessment	Justification
Did the research questions and inclusion criteria for the review include the components of PICO?	Yes	The study’s research questions and inclusion criteria incorporate the PICO components adequately.
Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?	Yes	The systematic review and meta-analysis were conducted in accordance with consensus guidelines and were reported according to the recommendations of the PRISMA 2020 statement. The study protocol was registered and published in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022353852). This indicates that the authors worked with a written protocol with independent verification.
Did the review authors explain their selection of the study designs for inclusion in the review?	Yes, but they did not explicitly justify the inclusion of non-randomized studies or the restriction to RCTs.	The authors included both prospective and retrospective cohort studies that estimated the risk for ischemic stroke with hazard ratios (HRs) and 95% confidence intervals (CIs) derived from a multivariate Cox regression analysis. However, they did not explicitly justify the inclusion of non-randomized studies or the restriction to RCTs. The authors may have chosen to include these types of studies because they are observational in nature and can provide valuable information about the risk factors and outcomes of a disease in a real-world setting.
Did the review authors use a comprehensive literature search strategy?	Partial Yes	The authors seem to have used a comprehensive literature search strategy. The authors searched three databases: PubMed, Embase, and Cochrane Library. The missing or not adequately described elements are the exact keywords/MESH terms used, and the supplementary methods of literature search (published reviews, specialized registers, experts in the field, reviewing reference lists, and grey literature).
Did the review authors perform study selection in duplicate?	Partial Yes (because no Kappa score was provided)	The authors appear to have adhered to most of the requirements for study selection in duplicate. They independently performed study selection, and they used a consensus process to resolve disagreements. However, the text does not provide information about the Kappa score, so it’s uncertain whether the level of agreement between the reviewers would be classified as ‘strong’.
Did the review authors perform data extraction in duplicate?	No	The authors did use two independent reviewers to perform data extraction but they did not specify a consensus process for disagreements specifically during this phase, nor did they provide a Kappa score to indicate the degree of agreement between the two reviewers.
Did the review authors provide a list of excluded studies and justify the exclusions?	No	The authors of the systematic review and meta-analysis did not provide a list of excluded studies and did not justify the exclusions. Although the article provides detailed information on the number of articles initially identified and the number of articles that were finally included in the meta-analysis, there is no list or any explicit information on which articles were excluded after the full-text review and why.
Did the review authors describe the included studies in adequate detail?	Yes	The authors of the systematic review appear to have described the included studies in adequate detail. They have provided sufficient information on the study design, participants, interventions, and outcomes, which would allow readers to assess the generalizability of the results. The authors used a PICOS system to detail the population, intervention, comparison, outcome, and study design used in the eligible studies.
Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?	Yes	The authors of the systematic review used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias for the included studies. The NOS is a widely accepted tool for assessing the quality of non-randomized studies included in systematic reviews and meta-analyses.
Did the review authors report on the sources of funding for the studies included in the review?	No	The authors of the systematic review did not report on the sources of funding for the studies included in the review. There is no mention of whether the funding sources of the included studies could potentially influence the direction and strength of the study results. The authors also did not acknowledge whether the source of funding for a study can be associated with the direction and strength of the study results.
If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?	Yes	The authors seem to have used appropriate methods for the statistical combination of results in the meta-analysis, and the chosen method appears to be well justified in the context of the data being combined.
If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?	Yes	The authors of the systematic review and meta-analysis clearly addressed the potential impact of risk of bias in individual studies on the results of the meta-analysis. The authors assessed the risk of bias using the Newcastle‒Ottawa Scale (NOS), which is a widely accepted tool for assessing the quality of non-randomized studies in meta-analyses.
Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review?	Yes	The authors of the systematic review accounted for the risk of bias in individual studies when interpreting or discussing the results of the review. The authors used the Newcastle‒Ottawa Scale (NOS) to assess the risk of bias in each of the included studies. This scale is widely recognized and used in systematic reviews and meta-analyses, especially for non-randomized studies, and it evaluates the selection of participants, comparability of study groups, and outcome assessment.
Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?	Partial Yes	The authors of the systematic review did discuss and provide an explanation for the heterogeneity observed in the results of the review. However, the authors did not explicitly perform subgroup analyses or meta-regression to explore reasons for heterogeneity.
If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?	No	The authors used funnel plots as a method to investigate publication bias, as stated in the statistical analysis section: “Publication bias was evaluated by funnel plots”. However, the authors did not explicitly discuss the potential impact of the publication bias on the results of the review in the provided text, which is a necessary part of a complete investigation of publication bias. Thus, while they took steps to investigate and visualize publication bias, it isn’t clear whether they discussed its implications for their findings.
Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?	Yes	The authors reported a funding which they received for the study. The document includes a conflict of interest statement and funding statement.

Detailed assessment of Amstar 2.0 domains

Domain 1: Did the research questions and inclusion criteria for the review include the components of PICO?

Based on the provided text, the systematic review and meta-analysis appear to include all the components of PICO (Population, Intervention, Control group, and Outcome). Here’s how:

1. Population: The population is described as the “general population without stroke at baseline.” This is a clear definition of the population that the study is focusing on.

2. Intervention: The intervention is defined as “appropriate measurements of at least one marker of atrial cardiomyopathy.” The markers are further classified into three main categories, including electrocardiographic, imaging, and serum biomarkers.

3. Comparison: The comparison group is not explicitly mentioned in the text, but it can be inferred that the comparison is made between different levels of atrial cardiomyopathy markers (highest vs. lowest levels) and their association with the risk of ischemic stroke.

4. Outcome: The outcome is clearly defined as “incident ischemic stroke.” The study aims to estimate the risk for ischemic stroke with hazard ratios (HRs) and 95% confidence intervals (CIs) derived from a multivariate Cox regression analysis.

Therefore, the assessment for this domain is “Yes,” as all four elements of PICO are described in the report.

Domain 2: Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?

Based on the provided text, the systematic review and meta-analysis were conducted in accordance with consensus guidelines and were reported according to the recommendations of the PRISMA 2020 statement. The study protocol was registered and published in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022353852). This indicates that the authors worked with a written protocol with independent verification.

The authors also provide a detailed description of their methods, including their search strategy, eligibility criteria, study selection, data extraction, risk of bias assessment, and statistical analysis. They also provide a comprehensive presentation of their results, including the results of their search, characteristics of the studies, and associations between various parameters and the incidence of ischemic stroke.

There is no explicit statement about any significant deviations from the protocol. However, the detailed description of the methods and the results suggests that the authors followed their protocol closely.

Therefore, the assessment for this domain is ‘Yes’. The authors demonstrate that they worked with a written protocol with independent verification, and there is no evidence of significant deviations from the protocol.

Domain 3: Did the review authors explain their selection of the study designs for inclusion in the review?

Based on the provided text, the authors of the systematic review have explained their selection of study designs for inclusion in the review. They used the PICOS (Population, Intervention, Comparison, Outcome, and Study design) system for their eligibility criteria. The authors included both prospective and retrospective cohort studies that estimated the risk for ischemic stroke with hazard ratios (HRs) and 95% confidence intervals (CIs) derived from a multivariate Cox regression analysis.

The authors did not restrict their study to randomized controlled trials (RCTs) but instead included both prospective and retrospective cohort studies. However, they did not explicitly justify the inclusion of non-randomized studies or the restriction to RCTs. The authors may have chosen to include these types of studies because they are observational in nature and can provide valuable information about the risk factors and outcomes of a disease in a real-world setting.

Therefore, the assessment for this domain would be “Yes” for the explanation of the selection of study designs, but “No” for the justification of the inclusion of non-randomized studies or restriction to RCTs. The authors did not provide a clear justification for this choice in the provided text.

Domain 4: Did the review authors use a comprehensive literature search strategy?

Based on the provided text, the authors of the systematic review appear to have used a comprehensive literature search strategy. Here’s the evaluation according to the criteria you provided:

1. At least two bibliographic databases were searched: Yes, the authors searched three databases: PubMed, Embase, and Cochrane Library.

2. The report includes the years and databases examined: Yes, the authors searched the databases from 01/01/2002 to 06/08/2022.

3. Key words and/or MESH terms: The authors mention using a search syntax for concepts of ischemic stroke and cardiomyopathy markers, but the exact keywords or MESH terms are not provided in the text. However, they mention that the detailed search strategy is described in Supplementary Table 1, which is not provided here.

4. The full search strategy is available on request: The authors mention that the detailed search strategy is described in Supplementary Table 1, which suggests that the full search strategy is available, although not directly in the text.

5. The authors supplemented their searches by checking published reviews, specialized registers, experts in the field, and reviewing reference lists: The text does not explicitly mention these aspects. However, the authors followed the PRISMA 2020 statement and consensus guidelines, which typically recommend these practices.

6. Publications in all relevant languages were sought: Yes, the authors did not impose language restrictions on their search.

7. The authors searched the grey literature where necessary: The text does not explicitly mention the search of grey literature.

Based on the information provided, the authors seem to have used a comprehensive literature search strategy. However, without the detailed search strategy (Supplementary Table 1) and explicit mention of some elements (like checking published reviews, specialized registers, experts in the field, reviewing reference lists, and searching grey literature), it’s hard to fully confirm. Therefore, the assessment would be a “partial Yes”. The missing or not adequately described elements are the exact keywords/MESH terms used, and the supplementary methods of literature search (published reviews, specialized registers, experts in the field, reviewing reference lists, and grey literature).

Domain 5: Did the review authors perform study selection in duplicate?

Based on the information provided in the article, the authors of the systematic review performed study selection in duplicate.

The text states, “Two investigators (JHG and YFL) systematically and independently searched the databases using the search syntax for concepts of ischemic stroke and cardiomyopathy markers…” This statement suggests that the study selection process was carried out by two independent reviewers, which satisfies the requirement for duplicate study selection.

In terms of disagreement resolution, the methods section of the article notes: “Disagreements were resolved by discussion with a third reviewer (JZ) when necessary.” This indicates that a consensus process was indeed used in situations where the initial two reviewers had conflicting opinions about study selection.

However, it’s important to note that the article does not provide information about the Kappa score. Therefore, it’s unclear whether the agreement between the two reviewers reached a ‘strong’ level (0.80 or greater), as required in your assessment criteria.

In conclusion, the authors appear to have adhered to most of the requirements for study selection in duplicate. They independently performed study selection, and they used a consensus process to resolve disagreements. However, the text does not provide information about the Kappa score, so it’s uncertain whether the level of agreement between the reviewers would be classified as ‘strong’.

Assessment: Partial Yes (because no Kappa score was provided)

Domain 6: Did the review authors perform data extraction in duplicate?

Based on the provided information, the authors of the systematic review did perform data extraction in duplicate. This is confirmed in the “Data extraction” section, where the authors mention that two investigators independently performed data extraction and quality evaluation.

However, the authors have not mentioned explicitly the use of a consensus process in cases of disagreement during data extraction. Though they do mention that disagreements during the study selection process were resolved by discussion with a third reviewer, they do not specify this procedure for the data extraction process.

In addition, there is no mention of a Kappa score being used to evaluate the degree of agreement between the two reviewers during data extraction.

Thus, based on the available information, the assessment of whether data extraction was performed in duplicate according to your described criteria would be “No”. While the authors did use two independent reviewers to perform data extraction, they did not specify a consensus process for disagreements specifically during this phase, nor did they provide a Kappa score to indicate the degree of agreement between the two reviewers.

Domain 7: Did the review authors provide a list of excluded studies and justify the exclusions?

Based on the provided text, the authors of the systematic review and meta-analysis did not provide a list of excluded studies and did not justify the exclusions. Although the article provides detailed information on the number of articles initially identified and the number of articles that were finally included in the meta-analysis, there is no list or any explicit information on which articles were excluded after the full-text review and why. Therefore, the assessment for this domain would be “No”.

To improve the transparency and replicability of their findings, the authors should have included a list of studies that were considered for inclusion but were excluded, along with the reasons for their exclusion. If the list is too long to include in the report, making it available on request would have been a suitable alternative. This would have given readers a more complete understanding of their systematic review process and allowed them to evaluate the validity of the authors’ decisions to exclude certain studies.

Domain 8: Did the review authors describe the included studies in adequate detail?

Based on the provided text, the authors of the systematic review appear to have described the included studies in adequate detail. They have provided sufficient information on the study design, participants, interventions, and outcomes, which would allow readers to assess the generalizability of the results. The authors used a PICOS system to detail the population, intervention, comparison, outcome, and study design used in the eligible studies.

The setting and location of each study are not explicitly mentioned in the report, but they have been incorporated into a comprehensive table (Supplementary Table 3) summarizing the characteristics of each study, which includes the country of each study, the author names, year of publication, and the design of the study.

The authors have specified a detailed methodology covering their search strategy, eligibility criteria, study selection, data extraction, risk of bias assessment, and statistical analysis, which speaks to the rigor of their work. They have also detailed the results of their systematic review and meta-analysis, describing the basic characteristics of the studies, the number of studies that assessed each marker type, and the associations found between each marker and ischemic stroke.

While the document provided here does not include the actual tables and figures referenced in the text, it is mentioned that these are provided as supplementary materials, where the reader can find more detailed information on the studies.

Therefore, the assessment of this domain is ‘Yes’, as the authors have described the included studies in adequate detail, allowing the reader to assess the generalizability of the results. The missing setting and location details in the main body of the text appear to be available in the supplementary materials, providing a comprehensive view of the conducted studies.

Domain 9: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?

Assessment: Yes

Justification:

The authors of the systematic review used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias for the included studies. The NOS is a widely accepted tool for assessing the quality of non-randomized studies included in systematic reviews and meta-analyses. The tool rates studies based on selection of study groups, comparability of groups, and ascertainment of the exposure or outcome of interest for case-control or cohort studies. Scores range from 0 to 9, and studies with a score of 7 or above are generally considered to be of high quality. The authors of this review considered studies with an NOS score higher than 6 to be of high quality, which is a reasonable criterion.

The risk of bias assessment was carried out by two independent investigators. This is a recommended approach as it helps to ensure the accuracy and completeness of the assessment. The authors also described that disagreements were resolved through discussions with a third reviewer, which is a common practice to ensure objectivity and reach consensus.

The results of the risk of bias assessment were reported for each study. Among the cohort studies included in the meta-analyses, there were studies with NOS scores of 4, 5, and 6, which indicates that some studies were of lower quality, thus presenting a risk of bias.

Finally, the results of the risk of bias assessment were used in subsequent synthesis, as indicated by the sensitivity analyses which included only studies at low risk of bias. This is an appropriate use of the results of a risk of bias assessment, as it allows for the examination of how the inclusion of studies with a higher risk of bias may impact the overall findings of the review.

Overall, the authors used a satisfactory technique for assessing the risk of bias in individual studies included in the review. They used a formal and appropriate tool, reported the results of the risk of bias assessment for each study, performed the assessment with at least two independent assessors, used a consensus process for disagreements, and incorporated the results of the assessment into subsequent analysis.

Domain 10: Did the review authors report on the sources of funding for the studies included in the review?

Based on the text provided, the authors of the systematic review did not report on the sources of funding for the studies included in the review. There is no mention of whether the funding sources of the included studies could potentially influence the direction and strength of the study results. The authors also did not acknowledge whether the source of funding for a study can be associated with the direction and strength of the study results. Therefore, the assessment for this domain is “No”.

Key elements that are missing or not adequately described include:

1. Disclosure of the funding sources for each of the included studies.

2. Discussion or acknowledgment of the potential influence of funding sources on the research findings.

3. Analysis or commentary on patterns of results in relation to the sources of funding.

4. Implementation of any strategies to mitigate potential biases due to funding sources.

Domain 11: If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?

The authors of the systematic review used appropriate methods for the statistical combination of results in the performed meta-analysis. Here are the reasons why the statistical methods were appropriate:

1. Heterogeneity Assessment: The authors used the I2 statistic to evaluate the heterogeneity across the included studies, which is a widely accepted statistical measure in meta-analyses.

2. Choice of Model: Based on the level of heterogeneity, the authors chose between fixed-effects and random-effects models, which is an appropriate approach. They used a fixed-effects model when study heterogeneity was low and a random-effects model otherwise. This shows a suitable strategy to address variability across studies.

3. Handling of Missing Data: Although the authors do not explicitly describe how they handled missing data, the meta-analysis process tends to only include studies that report the necessary data, reducing the issue of missing data.

4. Combination of Different Study Designs: The authors included both prospective and retrospective cohort studies and pooled hazard ratios (HRs) as a measure of risk estimates, which is a suitable approach for combining these two types of study designs.

5. Sensitivity Analysis: The authors performed sensitivity analyses, which is important to understand the robustness of the results and to evaluate the impact of certain studies on the overall results.

6. Publication Bias: The authors evaluated potential publication bias using funnel plots, a common technique for visually assessing publication bias in meta-analyses.

Therefore, the authors seem to have used appropriate methods for the statistical combination of results in the meta-analysis, and the chosen method appears to be well justified in the context of the data being combined. Thus, the assessment is ‘Yes’.

Domain 12: If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?

Assessment: Yes

Justification: The authors of the systematic review and meta-analysis clearly addressed the potential impact of risk of bias in individual studies on the results of the meta-analysis. The authors assessed the risk of bias using the Newcastle‒Ottawa Scale (NOS), which is a widely accepted tool for assessing the quality of non-randomized studies in meta-analyses. According to the NOS scale, studies with a score higher than 6 were considered high quality, and those with lower scores were evaluated for specific biases.

Furthermore, the authors conducted sensitivity analyses to assess the robustness of their findings. These sensitivity analyses included:

1. Only including studies with patients free of clinical AF (Atrial Fibrillation).

2. Excluding studies that used ischemic stroke or TIA (Transient Ischemic Attack) as an outcome.

3. Including only studies at low risk of bias.

4. Omitting each study in turn.

This approach allows the researchers to understand how the exclusion of potentially biased studies impacts the overall conclusions of the meta-analysis.

Also, the authors tested for publication bias using funnel plots, which is a visual tool to check for the presence of bias in meta-analyses.

Therefore, the authors of this systematic review and meta-analysis have clearly demonstrated that they have considered the potential impact of risk of bias in individual studies on their results, and have used appropriate methods to assess this potential impact.

Domain 13: Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?

Assessment: Yes

Justification: The authors of the systematic review and meta-analysis clearly addressed the potential impact of risk of bias in individual studies on the results of the meta-analysis. The authors assessed the risk of bias using the Newcastle‒Ottawa Scale (NOS), which is a widely accepted tool for assessing the quality of non-randomized studies in meta-analyses. According to the NOS scale, studies with a score higher than 6 were considered high quality, and those with lower scores were evaluated for specific biases.

Furthermore, the authors conducted sensitivity analyses to assess the robustness of their findings. These sensitivity analyses included:

1. Only including studies with patients free of clinical AF (Atrial Fibrillation).

2. Excluding studies that used ischemic stroke or TIA (Transient Ischemic Attack) as an outcome.

3. Including only studies at low risk of bias.

4. Omitting each study in turn.

This approach allows the researchers to understand how the exclusion of potentially biased studies impacts the overall conclusions of the meta-analysis.

Also, the authors tested for publication bias using funnel plots, which is a visual tool to check for the presence of bias in meta-analyses.

Therefore, the authors of this systematic review and meta-analysis have clearly demonstrated that they have considered the potential impact of risk of bias in individual studies on their results, and have used appropriate methods to assess this potential impact.

Domain 14: Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?
From the provided text, it appears that the authors of the systematic review did discuss and provide an explanation for the heterogeneity observed in the results of the review. The authors used the I² statistic to assess the degree of heterogeneity among the studies included in the review, with defined categories to classify the degree of heterogeneity (insignificant, low, moderate, high). For instance, an I² value ≤ 25% indicates insignificant heterogeneity, 26–50% indicates low heterogeneity, 51% to 75% indicates moderate heterogeneity, and ≥76% indicates high heterogeneity.

The authors used a fixed-effects model when study heterogeneity was low, and a random-effects model when heterogeneity was moderate to high. They also conducted sensitivity analyses to assess the robustness of their results and to further explore sources of heterogeneity. The sensitivity analyses were conducted by only including studies with patients free of clinical AF, excluding studies that used ischemic stroke or TIA as an outcome, including only studies at low risk of bias, and omitting each study in turn.

However, the authors did not explicitly perform subgroup analyses or meta-regression to explore reasons for heterogeneity, at least from the information provided in the text. It might be that those analyses were not deemed necessary due to the nature of the data or they are presented elsewhere in the full text.

So, based on the provided text and in response to the specific criteria mentioned, I would assess this domain as a “Partial Yes”. The authors did explore heterogeneity and provide explanations for it to some extent, including sensitivity analyses to handle it, but there is no clear mention of subgroup analyses or meta-regression to further probe into the reasons for heterogeneity.

Domain 15: If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?

Based on the provided text, the authors of the systematic review did perform a quantitative synthesis, as they mention conducting a meta-analysis on multiple cohort studies. However, there is no explicit mention of an investigation of publication bias or small-study effects.

Specifically, the authors do not mention having used funnel plots, tests for small-study effects, or other appropriate methods to assess for publication bias. Furthermore, there’s no discussion provided regarding the likely impact of such bias on the review’s results. They only hint at possible publication bias in the context of studies where NT-proBNP was analyzed as a continuous variable, but do not substantiate this with any detailed examination or testing.

Therefore, I would assess that the authors did not carry out an adequate investigation of publication bias and did not discuss its likely impact on the results of the review. In order to fully evaluate this domain, the authors would need to employ recognized methods, such as funnel plots or Egger’s regression test, and then discuss the possible implications of any detected bias.

Domain 16: Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Based on the provided text, the authors of this systematic review reported no potential sources of conflict of interest. The document includes a conflict of interest statement and funding statement which are necessary elements to evaluate this domain. Therefore, the assessment of this domain is “Yes”.