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STUDY OBJECTIVES: Biological models suggest that obstructive sleep apnea (OSA) is potentially carcinogenic. We aimed to clarify the inconsistent epidemiological literature by considering various traditional and novel OSA severity indices. METHODS: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for observational or randomized studies of associations of OSA, measured by diagnostic codes or any index, each with all-cancer incidence or mortality in adults, compared with participants with no/mild OSA. Two reviewers independently selected studies, extracted data, and evaluated study bias using the Newcastle-Ottawa scale and quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). We performed inverse variance-weighted, random-effects meta-analyses and sensitivity analyses. RESULTS: We included 20 observational studies (5,340,965 participants), all with moderate/low bias, from 1,698 records. Based on T90 (sleep duration with oxygen saturation < 90%), patients with OSA who had moderate (T90 > 1.2%, hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.07–1.54) and severe nocturnal hypoxemia (T90 > 12%, HR = 1.43, 95% CI = 1.16–1.76) experienced 30%–40% higher pooled all-cancer risk than normoxemic patients, after multiple adjustment for covariates including obesity. Furthermore, severe nocturnal hypoxemia nearly tripled all-cancer mortality (HR = 2.66, 95% CI = 1.21–5.85). Patients with apnea-hypopnea index–defined severe OSA, but not moderate OSA, had higher all-cancer risk (HR = 1.18, 95% CI = 1.03–1.35) but similar all-cancer mortality as patients without OSA. An OSA diagnosis was not associated with all-cancer risk. Evidence quality ranged from low to moderate. Insufficient evidence was available on the oxygen desaturation index, lowest/median saturation, and arousal index. CONCLUSIONS: In patients with OSA, nocturnal hypoxemia is independently associated with all-cancer risk and mortality. Future studies should explore if risk differs by cancer type, and whether cancer screening and OSA treatment are beneficial. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=220836; Identifier: CRD42021220836. CITATION: Tan BKJ, Teo YH, Tan NKW, et al. Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis. J Clin Sleep Med. 2022;18(5):1427–1440.

RATIONALE In 2020, lung cancer was the leading cause of cancer deaths, and was the most common cancer in men. Though obstructive sleep apnea (OSA) has been postulated to be carcinogenic, epidemiological studies are inconclusive. OBJECTIVES We conducted this systematic review and meta-analysis to investigate the associations between OSA and the incidence and mortality of lung cancer. METHODS Four electronic databases (PubMed, Embase, Cochrane Library, and Scopus) were searched from inception till 6 June 2021 for randomized controlled trials and observational studies examining the association between sleep apnea and incident lung cancer. Two reviewers selected studies, extracted data, graded the risk of bias using the Newcastle-Ottawa scale and the quality of evidence using GRADE. Random-effects models were used to meta-analyze the maximally covariate-adjusted associations. RESULTS Seven studies were included in our systematic review; among which four were suitable for meta-analysis, comprising a combined cohort of 4,885,518 patients. Risk of bias was low to moderate. OSA was associated with a higher incidence of lung cancer (HR 1.25, 95%CI 1.02 to 1.53), with substantial heterogeneity (I²=97%). Heterogeneity was eliminated, with a stable pooled effect size, when including the three studies with at least 5 years of median follow-up (HR 1.32, 95%CI 1.27 to 1.37, I²=0%). CONCLUSIONS In this meta-analysis of 4,885,518 patients from four observational studies, patients with OSA had approximately 30% higher risk of lung cancer, compared to those without OSA. We suggest more clinical studies with longer follow-up as well as biological models of lung cancer be performed to further elucidate this relationship.

Background Melanoma is the most aggressive and lethal form of skin cancer. While emerging in-vivo evidence suggests that intermittent hypoxia, a hallmark feature of obstructive sleep apnea (OSA), may induce melanoma tumorigenesis, the epidemiological association between OSA and melanoma has been inconsistent. Methods We performed a literature search of PubMed, Embase, Scopus and Cochrane Library from inception until 6 June 2021. Two reviewers independently selected randomized trials or observational studies that reported the association of OSA with melanoma incidence or mortality in adults, in comparison to participants with no OSA. Two reviewers independently extracted relevant data and assessed the quality of evidence using the GRADE framework and the Newcastle–Ottawa Scale (NOS). We pooled data using an inverse variance-weighted meta-analysis and ran pre-specified subgrourp analyses. Results The meta-analysis included six studies out of 1897 records, comprising a combined cohort of 5,276,451 patients. All studies were adjusted for covariates, with majority of studies adjusting for age (N=5) and sex (N = 4). Compared to those without OSA, patients with OSA had 71% higher pooled hazards of melanoma (HR = 1.71; 95% CI: 1.08–2.69, I2 = 99%). Subgroup analyses for studies with (1) median follow-up duration of at least five years, (2) prospective study design, (3) adjustment for obesity yielded HRs of 1.88 (95%CI:1.32–2.67, N = 5), 1.11 (95%CI:0.77–1.60, N = 2) and 1.52 (95%CI:0.75–3.08, N = 3) respectively. One study investigating the relationship between OSA and melanoma mortality detected no association. There were insufficient studies to assess publication bias. Conclusions Meta-analysis of mainly retrospective observational studies, with significant heterogeneity, suggests increased melanoma incidence in OSA patients. Future studies should prospectively explore the differential risk of melanoma for varying OSA severity, and whether timely OSA treatment may mitigate this risk.

Obstructive sleep apnea (OSA) is a postulated carcinogen based on epidemiological associations with all-cancer incidence and non-thyroid biological models. However, associations with thyroid carcinoma are unclear.We included observational/randomized studies of associations of OSA with thyroid carcinoma incidence/mortality in adults, from four databases. Random-effects meta-analyses and the population attributable fraction (PAF; from published global OSA prevalence estimates) were computed.We included four observational studies (N = 2,839,325), all with moderate/low risk of bias. OSA diagnosis was associated with twofold incidence of thyroid carcinoma (pooled HR 2.32, 95% CI 1.35-3.98, IOSA is associated with higher thyroid carcinoma incidence, though this does not prove causation. Biological/clinical studies should investigate OSA severity in relation to thyroid carcinoma progression and mortality, stratified by tumor histology.

Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship.We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted meta-analysis and performed pre-specified subgroup analyses.We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03-1.80; N = 6, I² = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98-1.87; N = 5, I² = 96%) and 1.57 (95% CI, 1.14-2.18; N = 4; I² = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA.This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression.

ObjectiveTo clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste.DesignSystematic review and meta-analysis.Data sourcesPubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021.Review methodsTwo blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included.Data extraction and synthesisTwo reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery.Main outcome measuresThe primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste.Results18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I2=70%, τ2=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I2=67%, τ2=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I2=0.0-77.2%, τ2=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I2=0.0-72.1%, τ2=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I2=20%, τ2=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I2=78%, τ2=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I2=10%, τ22=0%, τ2ConclusionsA substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.Systematic review registrationPROSPERO CRD42021283922.

IMPORTANCE: Hearing loss (HL) and dual sensory loss (DSL) are prevalent, disabling, and associated with numerous age-related health conditions, including dementia and frailty. To date, no evidence-based summary of their mortality risk is available. OBJECTIVE: To clarify the epidemiological associations between HL/DSL and mortality. DATA SOURCES: PubMed, Embase, and Cochrane Library, from inception until June 18, 2021. STUDY SELECTION: Two blinded reviewers selected observational or interventional studies, published as full-length English articles in peer-reviewed journals, that reported the presence or severity of HL or DSL (ie, comorbid HL and vision loss), whether objectively measured or self-reported, in association with any mortality estimate, among adults 18 years and older. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data and evaluated study bias using the Newcastle-Ottawa Scale, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)/Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and a PROSPERO-registered protocol. The analysis pooled maximally adjusted estimates using mixed-effects models, measured heterogeneity using I(2), investigated sources of heterogeneity using meta-regression and subgroup meta-analyses, examined and adjusted for publication bias, performed influence and cumulative meta-analyses, and assessed evidence quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for all-cause, cardiovascular, or other mortality estimates. RESULTS: This review included 14 retrospective and 12 prospective observational studies (1 213 756 participants) from 3220 records. Risk of bias was low to moderate; exclusion of 3 high-risk studies did not alter conclusions. Hearing loss was associated with excess all-cause mortality (HR, 1.13; 95% CI, 1.07-1.19; I(2) = 77%; n = 21; 95% prediction interval [PI], 0.93-1.37) and cardiovascular mortality (HR, 1.28; 95% CI, 1.10-1.50; I(2) = 60%; n = 6; 95% PI, 0.84-1.96), while DSL was associated with larger excess risks (all-cause: HR, 1.40; 95% CI, 1.30-1.51; I(2) = 34%; n = 10; 95% PI, 1.18-1.66; cardiovascular: HR, 1.86; 95% CI, 1.31-2.65; I(2) = 0%; n = 2), after adjustment for demographics and comorbidities. Prespecified meta-regression sufficiently explained heterogeneity, with longer follow-up duration weakening the pooled association, leaving low (29%) residual heterogeneity. Meta-regression among audiometric studies showed a dose-response association (doubling of HR per 30-dB increase in HL). Self-reported and audiometric effect sizes were similar, with lower heterogeneity in the latter. Associations were robust to trim-and-fill adjustment for publication bias and single-study influence and cumulative meta-analyses. Associations with accident/injury, cancer, and stroke mortality were inconclusive, with only 1 to 3 studies. Overall evidence quality was moderate. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, HL and DSL were associated with excess all-cause and cardiovascular mortality. Physicians caring for patients with HL should consider its relevance to general health and longevity.