An umbrella review of systematic reviews and meta-analyses of observational investigations of obstructive sleep apnea and health outcomes

Purpose The previous analysis of systematic reviews and meta-analyses have illustrated that obstructive sleep apnea (OSA) is correlated with multiple health outcomes. In the present research, our main aim was to execute an umbrella review to assess the available evidence for the associations between OSA and health outcomes. Methods Herein, a meta-analysis of previous observational investigations that have reported associations between OSA and health outcomes in all human populations and settings was performed. We used these studies to execute an umbrella review of available meta-analyses and systematic reviews. Results Sixty-six articles comprising 136 unique outcomes were enrolled in this analysis. Of the 136 unique outcomes, 111 unique outcomes had significant associations (p < 0.05). Only 7 outcomes (coronary revascularization after PCI, postoperative respiratory failure, steatosis, alaninetrans aminase (ALT) elevation, metabolic syndrome (MS), psoriasis, and Parkinson’s disease) had a high quality of evidence. Twenty-four outcomes had a moderate quality of evidence, and the remaining 80 outcomes had a weak quality of evidence. Sixty-nine outcomes exhibited significant heterogeneity. Twenty-five outcomes exhibited publication bias. Sixty-three (95%) studies showed critically low methodological quality. Conclusion Among the 66 meta-analyses exploring 136 unique outcomes, only 7 statistically significant outcomes were rated as high quality of evidence. OSA may correlate with an increased risk of coronary revascularization after PCI, postoperative respiratory failure, steatosis, ALT elevation, MS, psoriasis, and Parkinson’s disease.


Introduction
Obstructive sleep apnea (OSA) is a prevalent but treatable chronic sleep disorder that is determined through episodes of sleep apnea and hypopnea during sleep and results in recurrent episodes of hypercapnia and hypoxemia [1][2][3]. OSA has a prevalence of between 5 and 20% depending on the population surveyed and the definition utilized [4,5]. The prevalence is also increasing due to an increase in body mass index which is one of its major predisposing factors. Apart from causing uncomfortable symptoms such as headache [6] and attention deficit [7], earlier studies indicated that OSA also contributed to the advancement of several diseases including hypertension [8], cardiovascular disease [9,10], and diabetes [11]. Recent studies have drawn consistent conclusions [12][13][14]. Recently, a great number of researches have explored the correlation between OSA and other diseases. Multiple investigations and meta-analyses have illustrated that OSA poses a threat to human health because it increases the risk of various diseases, including cancers [15][16][17], depression [18], laryngopharyngeal reflux disease [19], metabolic disease [20], Parkinson's disease [21], and chronickidney disease (CKD) [22].
These studies suggest a possible causal relationship between OSA and different health outcomes, indicating that OSA has a bad influence on human health. However, several factors are known to decrease the validity and strength Weiwei Chen and Yuting Li contributed equally to this work and should be considered co-first authors of reported evidence including publication bias, protocol design flaws, or inconsistencies of studies. Currently, there have been no systematic reviews that have accurately summarized and critically appraised existing studies. In the current study, an umbrella review was executed to comprehensively evaluate published systematic reviews and metaanalyses of observational researches that reported associations between OSA and health information. This work can provide important guidance in the diagnosis and treatment of OSA.

Materials and methods
The protocol of the research was registered with PROS-PERO (registration number: CRD42020220015) before the umbrella review began. A systematic exploration of the literature search was accomplished in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols [23].

Literature search
From initiation until November 23, 2020, literature searches were performed using online databases such as Embase, PubMed, the Cochrane Database of Systematic Reviews, and the Web of Science. Literature searches were independently conducted by two researchers (CZ and LG). The search terms applied were ("obstructive sleep apnea" OR "obstructive sleep apnea-hypopnea" OR "OSA" OR "OSAH") AND (Meta-Analysis[ptyp] OR metaanaly*[tiab] OR metaanaly*[tiab] OR Systematic review [ptyp] OR "systematic review" [tiab]). The references were manually screened to identify eligible articles to be included in the study. The article titles, abstracts, and the complete manuscripts of the identified paper were then further assessed. A discussion was used to resolve potential discrepancies; ST acted as an arbiter to deal with discrepancies that could not be resolved by discussion among the investigators.

Eligibility criteria and exclusion criteria
The eligibility of articles was based on a systematic search by the authors to identify the most pertinent studies. Only systematic reviews or meta-analyses on the basis of the epidemiological studies performed in humans were considered in the analysis. Diagnostic trials and meta-analyses of interventional trials were not performed as part of the current study. Furthermore, the abstracts of the conference on review questions were not included in the final analysis. The final systematic reviews and meta-analyses that were analyzed had to include the data of pooled summary effects(i.e., relative risks (RRs); odds ratios (ORs); hazard ratios (HRs); mean difference (MD); weighted mean difference (WMD); standard mean difference (SMD); and their 95% confidence intervals (CIs)), number of included researches, number of participants and cases, heterogeneity, and publication bias. Whenever more than one meta-analysis was executed using on the basis of the same outcome, the agreement with the main conclusions reported in the study were verified. When the reported conclusions were conflicting, the meta-analysis with the greatest number of investigations was considered.

Data extraction
For investigations to be eligible for inclusion in the meta-analysis, two researchers (WC and YL) independently extracted data from the articles. This included the first author, the number of included investigations, the year of publication, the study design, the whole numbers of cases, and participants. The reported relative summary risk evaluates (ORs, RRs, HRs, SMD, WMD, or MD) and the corresponding 95% CIs were extracted, for each eligible systematic review and metaanalysis. The values of p for the total pooled effects, Cochran Q measurement, Egger's measurement, and I 2 were extracted. Discrepancies in the analyses were resolved by discussion among the investigators.

Assessment of methodological quality
Two investigators (WC and YL) independently assessed the quality of the methods reported in the studies. This was performed using a 16-criteria checklist included in AMSTAR 2 [24]. AMSTAR 2 is a fundamental revision of the original instrument of AMSTAR which was devised to evaluate systematic reviews that included randomized controlled experiments. The AMSTAR 2 score is categorized as high in studies that have no or one noncritical weakness, moderate in surveys with more than one noncritical weakness, low when the study has only one serious flaw without or with noncritical weaknesses, and seriously low when a study has more than one serious flaw without or with nonserious weaknesses. Discrepancies between the AMSTARS 2 scores for the articles were resolved by discussion between the investigators.

Assessment of the evidence quality
Two investigators (WC and YL) independently evaluated the quality of the evidence conforming to the parameters that have previously been applied in various fields [25][26][27][28]. Discrepancies were resolved by discussion. First, p value for the estimate < 0.001 [29,30] and more than 1000 cases of the disease, which indicated fewer false-positive results. Second, I 2 < 50% and p value for Cochran Q test > 0.10, which indicated consistency of results. Third, p value for Egger's test > 0.10, which exhibited no evidence of smallstudy impacts. When all of the above criteria were satisfied, the strength of the epidemiologic evidence was rated as high. When 1 of the criterion was not satisfied and the p value for the estimate was < 0.001, the strength of the epidemiologic evidence was rated as moderate. Then, the rest was defined as weak (p < 0.05). The value of p for the evaluation can be assessed from the 95% confidence interval of the pooled impact estimate utilizing an established method [31] if it was not directly reported in the article.

Data analysis
From each of the published studies, the outcome data of the available meta-analyses was extracted along with the estimated summary effect at the corresponding 95% CI. The total impacts of the pooled meta-analysis were considered significant when the p-value was < 0.05. Heterogeneity was appraised by the I 2 test and Q test, publication bias was estimated by utilizing Egger's test, and both were considered significant at p < 0.1. Studies that did not have the heterogeneity or publication bias results were reanalyzed if raw data were available.

Characteristics of the meta-analyses
The outcomes of the systematic investigation and the selection of eligible investigations are summarized in Fig. 1. Overall, 1972 articles were searched from which 66 metaanalyses of observational investigations were identified that had 136 unique outcomes [21,22,. The 66 eligible non-overlapping meta-analyses had publication dates ranging from 2009 to 2020 and are summarized in Table 1. The median number of primary investigations per evidence synthesis was 7 (range 2-64). Furthermore, 1 meta-analysis [54] lacked the data of both participants and cases, and 2 meta-analyses [52,95] lacked the data of cases. Among the meta-analyses identified in this study, the median number of cases was 900 117,496) and the median number of participants was 2962 (170-56,746,100). An extensive      range of data were reported such as cardiovascular disorders (n = 31), cerebral and cerebrovascular disease (n = 7), mortality (n = 5), postoperative complications (n = 20), pregnancy-related disorders (n = 13), ophthalmic disorders (n = 8), digestive disorders (n = 13), endocrine and metabolic system disorders(n = 17), urological disorders (n = 7), and other data (n = 15) (Fig. 2).

Summary effect size
A brief explanation of the effects of the included meta-analysis is given in Table 1. Overall, 111 (82%) of the 136 data reported significant summary outcomes (p < 0.05). These associations relate to the outcomes of the following different systems: 29 meta-analyses in cardiovascular disorders, 5 in cerebral and cerebrovascular disease, 4 in mortality, 14 in postoperative complications, 8 in pregnancy-related disorders, 7 in ophthalmic disorders, 11 in digestive disorders, 14 in endocrine and metabolic system, 7 in urological disorders, and 12 in other outcomes. Therefore, it can be concluded that OSA can enhance the risk of disease and have adverse effects on human health.

Heterogeneity and publication bias
For heterogeneity, 5 results in 5 articles were reanalyzed owing to that they did not exhibit the outcomes of heterogeneity [

AMSTAR 2 and summary of evidence
The results for the evaluation of the methodological qualities of the 66 included articles are shown in Table 2. Only 3 (5%) studies were determined to be low; the remaining 63 (95%) studies were determined to be critically low (Fig. 3). Based on the AMSTAR 2 criteria, none of the investigations were graded as moderate or high quality. The outcomes of the evidence measurement are shown in Table 3. When a study did not present the result of heterogeneity and publication bias, the corresponding criteria were considered to be not satisfied. Among the 111 statistically significant outcomes, 7 (6%) showed high epidemiologic evidence, 24 (22%) showed moderate epidemiologic evidence, and the remaining 80 (72%) were rated as weak (Fig. 4).

Discussion
In the current umbrella review, we identified 66 metaanalyses of observational studies and evaluated the current evidence supporting an association between OSA and various health outcomes. Also, we provide an extensive overview of the available evidence and critically evaluate the methodological quality of the meta-analyses and the quality of evidence for all the reported associations. OSA increased the risk of 111 health outcomes, including  Among the 111 outcomes, 54 outcomes had serious heterogeneity between studies. These possible confounding parameters (e.g., sex, body mass index, age, method of assessing OSA, OSA severity, smoking, alcohol drinking, the region of study, and follow-up period) may be the cause of heterogeneity. Substantial heterogeneity led to unreliable results. Of the 111 health outcomes, 23 outcomes possessed a remarkable publication bias, demonstrating that some negative achievements were not presented. Several reasons were leading to publication bias. First, when people start a study, they tend to assume that a positive result may ensure their work complies with the hypothesis during publication. Second, positive results have a higher probability of being published compared to negative results. Third, the study population is only a small fraction of the actual population with the disease. According to AMSTAR 2 criteria, 95% of the studies included in this umbrella analysis had "critically low" methodological quality. The critical flaws considered the absence of a registered protocol, the absence of the risk of bias in the considered investigations, and the absence of consideration of the risk of bias in the included investigations when interpreting or discussing the achieved outcomes of each study. Moreover, none of the meta-analyses in this study explained details of the funding source that had supported the work. The majority of the evaluated meta-analyses had considerable heterogeneity and small-study impacts; these were the main reasons for the evidence rating downgrade.
An umbrella review is a more beneficial method compared to a normal systematic review or meta-analysis due to it representing an overall illustration of achievements for phenomena or special questions [96]. To our knowledge, we are the first to use this method to present a comprehensive critical literature appraisal on published associations between OSA and diverse health information. Also, our two authors systematically searched four scientific databases using a strong search strategy with clearly defined eligibility criteria and data extraction parameters. The quality of included systematic reviews was also evaluated through AMSTAR 2. This is a benchmark methodological quality measurement that is utilized to assessing the quality of the methods utilized for meta-analyses. Furthermore, we graded the epidemiologic evidence conforming to established, prespecified criteria. Its criteria included an assessment of heterogeneity, publication bias, and precision of the estimate, which is more objective than the GRADE system criteria.
There are some limitations in our umbrella review. First, in this analysis, we explained associations evaluated through the meta-analyses of observational investigations. In doing so, we may have missed other health outcomes that have not yet been investigated by meta-analyses. Second, this umbrella analysis included systematic reviews and meta-analyses that were only published in English. The potential missing information in other languages could influence the assessment outcomes. Third, the majority of the meta-analyses had heterogeneity; observational researches are susceptible to uncertainty and confounding bias.

Conclusions
The associations between OSA and an extensive range of health information have been broadly reported in many meta-analyses. Based on our umbrella review, 66 meta-analyses explored 136 unique outcomes, only 7 outcomes showed a high level of epidemiologic evidence with statistical significance. OSA could be associated with the enhanced risk of coronary revascularization after PCI, postoperative respiratory failure, steatosis,         Overall, OSA is harmful to human health but will need further exploration on this topic with high-quality prospective studies.