Do sex differences in the prevalence of ECG abnormalities vary across ethnic groups living in the Netherlands? A cross-sectional analysis of the population-based HELIUS study

Objectives Major ECG abnormalities have been associated with increased risk of cardiovascular disease (CVD) burden in asymptomatic populations. However, sex differences in occurrence of major ECG abnormalities have been poorly studied, particularly across ethnic groups. The objectives were to investigate (1) sex differences in the prevalence of major and, as a secondary outcome, minor ECG abnormalities, (2) whether patterns of sex differences varied across ethnic groups, by age and (3) to what extent conventional cardiovascular risk factors contributed to observed sex differences. Design Cross-sectional analysis of population-based study. Setting Multi-ethnic, population-based Healthy Life in an Urban Setting cohort, Amsterdam, the Netherlands. Participants 8089 men and 11 369 women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged 18–70 years without CVD. Outcome measures Age-adjusted and multivariable logistic regression analyses were performed to study sex differences in prevalence of major and, as secondary outcome, minor ECG abnormalities in the overall population, across ethnic groups and by age-groups (18–35, 36–50 and >50 years). Results Major and minor ECG abnormalities were less prevalent in women than men (4.6% vs 6.6% and 23.8% vs 39.8%, respectively). After adjustment for conventional risk factors, sex differences in major abnormalities were smaller in ethnic minority groups (OR ranged from 0.61 in Moroccans to 1.32 in South-Asian Surinamese) than in the Dutch (OR 0.49; 95% CI 0.36 to 0.65). Only in South-Asian Surinamese, women did not have a lower odds than men (OR 1.32; 95% CI 0.96 to 1.84). The pattern of smaller sex differences in ethnic minority groups was more pronounced in older than in younger age-groups. Conclusions The prevalence of major ECG abnormalities was lower in women than men. However, sex differences were less apparent in ethnic minority groups. Conventional risk factors did not contribute substantially to observed sex differences.

modest differences observed in major ECG abnormalitiessuggest that this is amended. The Introduction sets the scene and provides a clear rationale however there appear to be additional studies that have considered gender / sex differences from a quick search of the literature that have not been referenced in this manuscript therefore the statements that there are only should be modified / clarifies eg Ethnic and Gender Specific Differences Among Athletes Participating in ECG Screening -American College of Cardiology https://www.acc.org/latest-incardiology/articles/2016/08/25/12/25/ethnic-and-gender-specificdifferences-among-athletes-participating-in-ecg-screening#.XsZbRfiOhIs.twitter Methods: It would be useful to see a study flow diagram in the manuscript or as an appendix if space is limited to show account for numbers included in the analysis. Discussion: caution re over-interpretation of the findings. Query the rational for the structure of the discussion section i.e. placing strengths and limitations after the opening paragraph however this is an editorial decision. The authors highlight the issue of 'classification' of major and minorthis is a significant issue given the relatively small percentages reported and modest difference between groups, are the authors expand the discussion section to give further consideration to this limitation. The implications of the study have been highlighted however the authors have not included a clear conclusion based on the findings reported. Strobe guidelines considered.

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 Reviewer Name: Zehuai Wen Institution and Country: Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine Please state any competing interests or state 'None declared': None declared.
Please leave your comments for the authors below The study used the data from the HELIUS study to explore sex differences in the prevalence of ECG abnormalities in adults living in Amsterdam. This is an interesting survey in this field to answer a gap question. The report of the study followed the principles of the STROBE statement. Only minor comments are below. REPLY: We thank the reviewer for acknowledging the interest of the topic.
1.It is best to have a brief introduction to stratification random sampling method described in the manuscript. REPLY: We have clarified the random sampling method in the method section. In addition, we included an additional reference to the design paper of the HELIUS study to provide more information on development of the cohort: 'The HELIUS study has been described in detail elsewhere. [16,17]. Briefly, baseline data collection took place between 2011 and 2015 and included participants of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan, and Turkish origin aged 18-70 years living in Amsterdam. Potential participants were sampled with a simple random sampling method from the municipality registry, after stratification by ethnicity as defined by registered country of birth.
[18]' 2.For the statistical analyses section, the dependent variable is major or minor ECG abnormalities, does it consider a multinomial logistic regression with a three-categories dependent variable of ECG abnormalities? REPLY: We have performed binary logistic regression analyses with any major ECG abnormalities (yes/no) and any minor ECG abnormalities (yes/no) as separate outcomes. We considered multinomial logistic regression not to be appropriate since major ECG abnormalities and minor ECG abnormalities are not mutually exclusive, i.e., they can co-occur. We clarified this in the method section: 'We performed binary logistic regression analyses with hierarchal models to examine sex differences in prevalence of 1) any major ECG abnormalities and 2) any minor ECG abnormalities, adjusted for ...' Reviewer: 2 Reviewer Name: Professor Mary Ward Institution and Country: Ulster University, Cromore Rd, Coleraine, BT52 1SA Please state any competing interests or state 'None declared': None declared Please leave your comments for the authors below This is a well written manuscript that investigates sex differences in the prevalence of ECG abnormalities across ethnic groups in the HELIUS cohort. The cross sectional study includes data on almost 20,000 adults from this multi-ethnic, population based study and reports that women have a lower prevalence of major ECG abnormalities than men, which is consistent with previous literature in the field. This is one of a many studies published on this cohort by the research group and presents new data to add to the evidence base, particularly regarding the differences by ethnic group. Strengths and litigations have been identified, including the size of the cohort which facilitates meaningful sub-analysis. 1. The paper is well written and the abstract is clear although care should be taken not to over extrapolate the conclusion given the modest differences observed in major ECG abnormalitiessuggest that this is amended. REPLY: We thank the reviewer for acknowledging the interest of the topic. We describe the prevalence of ECG abnormalities in a healthy, general population sample (from which people with known CVD were excluded). Although the differences may appear modest in absolute terms, we consider the relative differences relevant as they translate to substantial numbers at a population level. Nevertheless, we have reformulated our conclusion: 'The prevalence of major ECG abnormalities was lower in women than men. However, sex differences were less apparent in ethnic minority groups. Conventional risk factors did not contribute substantially to observed sex differences.' 2. The Introduction sets the scene and provides a clear rationale however there appear to be additional studies that have considered gender / sex differences from a quick search of the literature that have not been referenced in this manuscript therefore the statements that there are only should be modified / clarifies eg Ethnic and Gender Specific Differences Among Athletes Participating in ECG Screening -American College of Cardiology https: //eur04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.acc.org%2Flatest-in-cardiology%2Farticles%2F2016%2F08%2F25%2F12%2F25%2Fethnic-and-gender-specificdifferences-among-athletes-participating-in-ecg-screening%23.XsZbRfiOhIs.twitter&data=02%7C01%7Cr.bolijn%40amsterdamumc.nl%7C6d66457c5 d3b46cb78fa08d803ebd8d8%7C68dfab1a11bb4cc6beb528d756984fb6%7C0%7C0%7C6372636587 80694462&sdata=p0ee2N%2B6%2Blx4L9Z0lns45qGWR90MzcF66zGQEBKt8Cc%3D&reserved=0 REPLY: We thank the reviewer for this suggestion. Although this is an interesting article, it focusses on ECG criteria for preparticipation screening in athletes. Athletes represent a selective subgroup, as they are generally younger and healthier than the general population. Therefore, different ECG criteria may be applicable and another classification of abnormalities may be relevant. Since our study focusses on differences in ECG abnormalities in the general population, we consider this paper to be less applicable. We have clarified in the introduction section that the focus of our study is on sex differences in ECG abnormalities in the general population: 'Although studies have described the prevalence of major ECG abnormalities in men and women from diverse general populations, [5][6][7][8][9][10][11] only three studied sex differences in general populations specifically. [5][6][7]' To be certain that we indeed did not miss general population studies, we have repeated our literature search and rechecked the reference lists of included papers for potentially relevant papers on sex differences in ECG abnormalities. However, this did not yield additional papers to be included in our manuscript.
3. Methods: It would be useful to see a study flow diagram in the manuscript or as an appendix if space is limited to show account for numbers included in the analysis.