Publications by authors named "Daniel J Gottlieb"

171 Publications

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.

Genome Med 2021 08 26;13(1):136. Epub 2021 Aug 26.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
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http://dx.doi.org/10.1186/s13073-021-00917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394596PMC
August 2021

Referral of adults with obstructive sleep apnea for surgical consultation: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

J Clin Sleep Med 2021 Aug 5. Epub 2021 Aug 5.

American Academy of Sleep Medicine, Darien, IL.

Introduction: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the referral of adults with obstructive sleep apnea (OSA) for surgical consultation.

Methods: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of upper airway sleep apnea surgery or bariatric surgery to no treatment as well as studies that reported on patient-important and physiologic outcomes pre- and postoperatively. Statistical analyses were performed to determine the clinical significance of using surgery to treat obstructive sleep apnea in adults. Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations.

Results: The literature search resulted in 274 studies that provided data suitable for statistical analyses. The analyses demonstrated that surgery as a rescue therapy results in a clinically significant reduction in excessive sleepiness, snoring, blood pressure (BP), apnea-hypopnea index (AHI), respiratory disturbance index (RDI), oxygen desaturation index (ODI), increase in lowest oxygen saturation (LSAT), sleep quality, and improvement in quality of life in adults with OSA who are intolerant or unaccepting of positive airway pressure (PAP) therapy. The analyses demonstrated that surgery as an adjunctive therapy results in a clinically significant reduction in optimal PAP pressure and improvement in PAP adherence in adults with OSA who are intolerant or unaccepting of PAP due to side effects associated with high pressure requirements. The analyses also demonstrated that surgery as an initial treatment results in a clinically significant reduction in AHI/RDI, sleepiness, snoring, BP, and ODI, and increase in LSAT in adults with OSA and major anatomical obstruction. Analysis of bariatric surgery data showed a clinically significant reduction in BP, AHI/RDI, sleepiness, snoring, optimal PAP level, BMI, ODI, and an increase in LSAT in adults with OSA and obesity. Analyses of very limited evidence suggest that upper airway surgery does not result in a clinically significant increase in risk of serious persistent adverse events and suggested that bariatric surgery may result in a clinically significant risk of iron malabsorption that may be managed with iron supplements. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations.
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http://dx.doi.org/10.5664/jcsm.9594DOI Listing
August 2021

Referral of adults with obstructive sleep apnea for surgical consultation: an American Academy of Sleep Medicine clinical practice guideline.

J Clin Sleep Med 2021 Aug 5. Epub 2021 Aug 5.

American Academy of Sleep Medicine, Darien, IL.

Introduction: This guideline establishes clinical practice recommendations for referring adults with obstructive sleep apnea (OSA) for surgical consultation.

Methods: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine, otolaryngology, and bariatric surgery to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force evaluated the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.

Recommendations: The following recommendations are intended as a guide for clinicians who treat adults with OSA. Each recommendations statement is assigned a strength ("Strong" or "Conditional"). A "Strong" recommendation (i.e., "We recommend…") is one that clinicians should follow under most circumstances. A "Conditional" recommendation is one that requires that the clinician use clinical knowledge and experience, and strongly consider the patient's values and preferences to determine the best course of action. 1. We recommend that clinicians discuss referral to a sleep surgeon with adults with OSA and BMI<40 who are intolerant or unaccepting of PAP as part of a patient-oriented discussion of alternative treatment options. (STRONG) 2. We recommend that clinicians discuss referral to a bariatric surgeon with adults with OSA and obesity (class II/III, BMI ≥35) who are intolerant or unaccepting of PAP as part of a patient-oriented discussion of alternative treatment options. (STRONG) 3. We suggest that clinicians discuss referral to a sleep surgeon with adults with OSA, BMI<40, and persistent inadequate PAP adherence due to pressure-related side effects as part of a patient-oriented discussion of adjunctive or alternative treatment options. (CONDITIONAL) 4. We suggest clinicians recommend PAP as initial therapy for adults with OSA and a major upper airway anatomic abnormality prior to consideration of referral for upper airway surgery. (CONDITIONAL).
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http://dx.doi.org/10.5664/jcsm.9592DOI Listing
August 2021

BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Framingham Heart Study, Framingham, MA, USA.

Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.
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http://dx.doi.org/10.1016/j.xhgg.2021.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321319PMC
July 2021

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

The Framingham Heart Study, Framingham, Massachusetts, USA.

Introduction: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk.

Methods: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status.

Results: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers.

Discussion: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.
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http://dx.doi.org/10.1002/alz.12405DOI Listing
July 2021

Irregular hospital discharge from acute inpatient and residential mental health treatment settings in a large integrated healthcare system.

Gen Hosp Psychiatry 2021 Sep-Oct;72:7-14. Epub 2021 Jun 26.

Veterans Affairs Medical Center, 215 North Main Street, White River Junction, VT 05009, USA; Geisel School of Medicine at Dartmouth College, 1 Rope Ferry Road, Hanover, NH 03755, USA; National Center for PTSD, 215 North Main Street, White River Junction, VT 05009, USA. Electronic address:

Objective: Irregular discharge is a concern among mental health populations and associated with poor outcomes. Little is known about the relationship between irregular discharge and treatment setting. Because care processes differ between acute inpatient and residential settings, it is important to evaluate irregular discharge in these settings.

Method: A retrospective study was conducted in patients with mental health conditions admitted to acute inpatient or residential mental health settings in the Department of Veterans Affairs, 2003-2019. Logistic regression and multivariate Cox proportional hazards were used to evaluate factors associated with irregular discharge risk in the first 90- days of admission.

Results: Among 1.8 million discharges, 7.4% had an irregular discharge within 90- days of admission. Younger age was a central predictor of risk. Irregular discharge rates were four-fold higher in residential versus acute settings. When accounting for length of stay (LOS) across settings, there was a modest higher risk of irregular discharge from acute versus residential settings (HR = 1.06, 95% Confidence Interval 1.04-1.07).

Conclusions: Patients are at high risk for irregular discharge from acute and residential settings when they are young. LOS is an important determinant of irregular discharge risk.. Interventions are needed to address drivers of irregular discharge.
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http://dx.doi.org/10.1016/j.genhosppsych.2021.06.009DOI Listing
June 2021

Sex differences within symptom subtypes of mild obstructive sleep apnea.

Sleep Med 2021 08 9;84:253-258. Epub 2021 Jun 9.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Objectives: Prior studies have identified symptom subtypes of moderate to severe (AHI >15) obstructive sleep apnea (OSA). They have not yet been consistently examined in those with mild OSA (AHI 5-15 events/hour). This is important as women are more likely than men to present with mild OSA and may present with different OSA symptoms. The objectives of this study were to determine 1) symptom subtypes in mild OSA and 2) if there are sex differences in the distribution of subtypes.

Methods: The sample included men (n = 921) and women (n = 797) with mild OSA, aged 39-90 years, evaluated with a single night of in-home polysomnography as part of the Sleep Heart Health Study. Latent class analysis determined symptom subtypes. Testing for sex differences relative to OSA severity and symptom subtype used chi-squared test for independence. Bonferroni corrected z-tests compared column proportions.

Results: Symptom subtypes of mild OSA were not significantly different than those identified in prior studies of moderate-severe OSA (p > 0.05): minimally symptomatic (36.4%), disturbed sleep (11.6%), moderately sleepy (37%), and excessively sleepy (15%), p > 0.05. Sex differences within the symptom subtypes were significant [χ(df = 3) = 30.04, p < 0.001, Cramer's V = 0.132]. Relative to men, women were more likely to be in the disturbed sleep subtype (p < 0.05), and the excessively sleepy subtype (p < 0.05) while less likely to be in the moderately sleep (<0.05) subtype. Women and men were equally represented in the minimal symptoms subtype (p > 0.05).

Conclusions: Results suggest symptom reporting among individuals with mild OSA differs as a function of sex. These data have important clinical implications for screening men and women for OSA.
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http://dx.doi.org/10.1016/j.sleep.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364755PMC
August 2021

The AHI is useful but limited: how can we do better?

Sleep 2021 09;44(9)

VA Boston Healthcare System and Brigham & Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1093/sleep/zsab150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577216PMC
September 2021

A composite sleep and pulmonary phenotype predicting hypertension.

EBioMedicine 2021 Jun 15;68:103433. Epub 2021 Jun 15.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston MA 02115, room 225C, USA. Electronic address:

Background: Multiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment.

Methods: To use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS).

Findings: At baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]).

Interpretation: A unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension.

Funding: This research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.
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http://dx.doi.org/10.1016/j.ebiom.2021.103433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217680PMC
June 2021

A composite sleep and pulmonary phenotype predicting hypertension.

EBioMedicine 2021 Jun 15;68:103433. Epub 2021 Jun 15.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston MA 02115, room 225C, USA. Electronic address:

Background: Multiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment.

Methods: To use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS).

Findings: At baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]).

Interpretation: A unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension.

Funding: This research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.
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http://dx.doi.org/10.1016/j.ebiom.2021.103433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217680PMC
June 2021

A composite sleep and pulmonary phenotype predicting hypertension.

EBioMedicine 2021 Jun 15;68:103433. Epub 2021 Jun 15.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston MA 02115, room 225C, USA. Electronic address:

Background: Multiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment.

Methods: To use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS).

Findings: At baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]).

Interpretation: A unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension.

Funding: This research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.
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http://dx.doi.org/10.1016/j.ebiom.2021.103433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217680PMC
June 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517040PMC
April 2021

Metrics of sleep apnea severity: beyond the apnea-hypopnea index.

Sleep 2021 07;44(7)

Medical service, VA Boston Healthcare System, Boston, MA.

Obstructive sleep apnea (OSA) is thought to affect almost 1 billion people worldwide. OSA has well established cardiovascular and neurocognitive sequelae, although the optimal metric to assess its severity and/or potential response to therapy remains unclear. The apnea-hypopnea index (AHI) is well established; thus, we review its history and predictive value in various different clinical contexts. Although the AHI is often criticized for its limitations, it remains the best studied metric of OSA severity, albeit imperfect. We further review the potential value of alternative metrics including hypoxic burden, arousal intensity, odds ratio product, and cardiopulmonary coupling. We conclude with possible future directions to capture clinically meaningful OSA endophenotypes including the use of genetics, blood biomarkers, machine/deep learning and wearable technologies. Further research in OSA should be directed towards providing diagnostic and prognostic information to make the OSA diagnosis more accessible and to improving prognostic information regarding OSA consequences, in order to guide patient care and to help in the design of future clinical trials.
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http://dx.doi.org/10.1093/sleep/zsab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271129PMC
July 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Small Area Analysis of Veterans Affairs Mental Health Services Data.

Psychiatr Serv 2021 04 3;72(4):384-390. Epub 2021 Feb 3.

Department of Veterans Affairs (VA) Medical Center, White River Junction, Vermont.

Objective: To identify geographic variation in mental health service use in the Department of Veterans Affairs (VA), the authors constructed utilization-based VA mental health service areas (MHSAs) for outpatient treatment and mental health referral regions (MHRRs) for residential and acute inpatient treatment.

Methods: MHSAs are empirically derived geographic groupings of one or more counties containing one or more VA outpatient mental health clinics. For each county within an MHSA, patients received most of their VA-provided outpatient mental health care within that MHSA. MHSAs were aggregated into MHRRs according to where VA users in each MHSA received most of their residential and acute inpatient mental health care. Attribution loyalty was evaluated with the localization index-the fraction of VA users living in each geographic area who used their designated MHSA and MHRR facility. Variation in outpatient mental health visits and in acute inpatient and residential mental health stays was determined for the 2008-2018 period.

Results: A total of 441 MHSAs were aggregated to 115 MHRRs (representing 3,909,080 patients with 52,372,303 outpatient mental health visits). The mean±SD localization index was 59.3%±16.4% for MHSAs and 67.8%±12.7% for MHRRs. Adjusted outpatient mental health visits varied from a mean of 0.88 per year in the lowest quintile of MHSAs to 3.14 in the highest. Combined residential and acute inpatient days varied from 0.29 to 1.79 between the lowest and highest quintiles.

Conclusions: MHSAs and MHRRs validly represented mental health utilization patterns in the VA and displayed considerable variation in mental health service provision across different locations.
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http://dx.doi.org/10.1176/appi.ps.202000130DOI Listing
April 2021

Interleukin-6 Interacts with Sleep Apnea Severity when Predicting Incident Alzheimer's Disease Dementia.

J Alzheimers Dis 2021 ;79(4):1451-1457

The Framingham Heart Study, Framingham, MA, USA.

Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer's type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.
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http://dx.doi.org/10.3233/JAD-200545DOI Listing
September 2021

Hospital-based health systems 20 years later: A taxonomy for policy research and analysis.

Health Serv Res 2021 06 11;56(3):453-463. Epub 2021 Jan 11.

The Dartmouth Institute for Health Policy, Dartmouth University, Lebanon, New Hampshire, USA.

Objective: Building on the original taxonomy of hospital-based health systems from 20 years ago, we develop a new taxonomy to inform emerging public policy and practice developments.

Data Sources: The 2016 American Hospital Association's (AHA) Annual Survey; the 2016 IQVIA Healthcare Organizations and Systems (HCOS) database; and the 2017-2018 National Survey of Healthcare Organizations and Systems (NSHOS).

Study Design: Cluster analysis of the 2016 AHA Annual Survey data to derive measures of differentiation, centralization, and integration to create categories or types of hospital-based health systems.

Data Collection: Principal components factor analysis with varimax rotation generating the factors used in the cluster algorithms.

Principal Findings: Among the four cluster types, 54% (N = 202) of systems are decentralized (-0.35) and relatively less differentiated (-0.37); 23% of systems (N = 85) are highly differentiated (1.28) but relatively decentralized (-0.29); 15% (N = 57) are highly centralized (2.04) and highly differentiated (0.65); and approximately 9 percent (N = 33) are least differentiated (-1.35) and most decentralized (-0.64). Despite differences in calculation, the Highly Centralized, Highly Differentiated System Cluster and the Undifferentiated, Decentralized System Cluster were similar to those identified 20 years ago. The other two system clusters contained similarities as well as differences from those 20 years ago. Overall, 82 percent of the systems remain relatively decentralized suggesting they operate largely as holding companies allowing autonomy to individual hospitals operating within the system.

Conclusions: The new taxonomy of hospital-based health systems bears similarities as well as differences from 20 years ago. Important applications of the taxonomy for addressing current challenges facing the healthcare system, such as the transition to value-based payment models, continued consolidation, and the growing importance of the social determinants of health, are highlighted.
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http://dx.doi.org/10.1111/1475-6773.13621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143673PMC
June 2021

The Sleep Apnea-Specific Pulse-Rate Response Predicts Cardiovascular Morbidity and Mortality.

Am J Respir Crit Care Med 2021 06;203(12):1546-1555

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts.

Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (ΔHR). We measured the ΔHR in the MESA (Multi-Ethnic Study of Atherosclerosis) ( = 1,395) and the SHHS (Sleep Heart Health Study) ( = 4,575). MESA data were used to determine the functional form of the association between the ΔHR and subclinical cardiovascular biomarkers, whereas primary analyses tested the association of the ΔHR with nonfatal or fatal cardiovascular disease (CVD) and all-cause mortality in longitudinal data from the SHHS. In the MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium, NT-proBNP [N-terminal prohormone BNP], and Framingham risk score) and the ΔHR; notably, a high ΔHR (upper quartile) was associated with elevated biomarker scores compared with a midrange ΔHR (25th-75th centiles). In the SHHS, individuals with a high ΔHR compared with a midrange ΔHR were at increased risk of nonfatal or fatal CVD and all-cause mortality (nonfatal adjusted hazard ratio [95% confidence interval (CI)], 1.60 [1.28-2.00]; fatal adjusted hazard ratio [95% CI], 1.68 [1.22-2.30]; all-cause adjusted hazard ratio [95% CI], 1.29 [1.07-1.55]). The risk associated with a high ΔHR was particularly high in those with a substantial hypoxic burden (nonfatal, 1.93 [1.36-2.73]; fatal, 3.50 [2.15-5.71]; all-cause, 1.84 [1.40-2.40]) and was exclusively observed in nonsleepy individuals. Individuals with OSA who demonstrate an elevated ΔHR are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.
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http://dx.doi.org/10.1164/rccm.202010-3900OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483223PMC
June 2021

Slow-Wave Sleep and MRI Markers of Brain Aging in a Community-Based Sample.

Neurology 2021 03 22;96(10):e1462-e1469. Epub 2020 Dec 22.

From the Framingham Heart Study (A.-A.B., A.S.B., J.R.R., C.L.S., J.M.Z., S.S., M.P.P. J.J.H.); Department of Neurology (A.-A.B., A.S.B., C.L.S., S.S., J.J.H.), Boston University School of Medicine; Department of Biostatistics (A.S.B., J.J.H. ), Boston University School of Public Health, MA; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (V.M., C.L.S., S.S., J.J.H.), and Department of Population Health Sciences (J.J.H.), University of Texas Health Sciences Center, San Antonio; Centre for Advanced Research in Sleep Medicine (E.S.), Hôpital du Sacré-Coeur de Montréal, CIUSSS-NIM; Department of Neuroscience (E.S.), Université de Montréal, Quebec, Canada; Department of Neurology (C.D., P.M.), and School of Medicine and Imaging of Dementia and Aging Laboratory, Center for Neuroscience (P.M.), University of California, Davis, Sacramento; Division of Sleep and Circadian Disorders (S.R., D.J.G.), Brigham & Women's Hospital; Beth Israel Deaconess Medical Center (S.R., D.J.G.); Division of Sleep Medicine Harvard Medical School, Boston, MA; VA Boston Healthcare System (D.J.G.), Boston, MA; Turner Institute for Brain and Mental Health (M.P.P.), School of Psychological Sciences, Monash University, Melbourne, VIC, Australia; and Harvard T.H. Chan School of Public Health (M.P.P.), Boston, MA.

Objective: To test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI.

Methods: We studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression.

Results: Less slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], = 0.015; percentage, 0.16 [0.08], = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], = 0.034), and higher white matter hyperintensities volume (absolute duration, -0.12 [0.05], = 0.010; percentage, -0.10 [0.04], = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts.

Conclusion: Loss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep.
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http://dx.doi.org/10.1212/WNL.0000000000011377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055313PMC
March 2021

Benefits of Treating Obstructive Sleep Apnea-Reply.

JAMA 2020 09;324(11):1110-1111

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jama.2020.11856DOI Listing
September 2020

Systemic inflammation as a moderator between sleep and incident dementia.

Sleep 2021 02;44(2)

The Framingham Heart Study, Framingham, MA.

Study Objectives: To determine whether C-reactive protein (CRP), a marker of systemic inflammation, moderates the association between sleep and incident dementia.

Methods: We studied Framingham Heart Study participants who completed at baseline a serum CRP assessment and in-home polysomnography to measure sleep duration, sleep efficiency, sleep latency, wake after sleep onset (WASO), number of awakenings, arousal index, and apnea-hypopnea index. Participants were divided into groups according to their CRP level: low (<1 mg/L), average (1-3 mg/L), and high inflammation (>3 mg/L). Surveillance for outcomes (incident all-cause and Alzheimer's disease [AD] dementia) commenced at baseline and continued up to 22.5 years.

Results: In 291 participants (mean age 67.5 ± 4.9 years, 51.6% men) followed for 13.4 ± 5.4 years, we observed 43 cases of all-cause dementia, 33 of which were clinically consistent with AD. Whereas no direct association between CRP or sleep exposures was observed with incident dementia, CRP levels interacted with nighttime wakefulness when predicting both incident all-cause and AD dementia. In the high CRP group, longer WASO (hazard ratio [HR], 2.89; 95% CI, 1.31-6.34) and more nighttime awakenings (HR, 4.55; 95% CI, 1.19-17.38) were associated with higher risk of incident dementia. In the low CRP group, fewer nighttime awakenings were associated with a higher risk of incident dementia (HR, 0.07; 95% CI, 0.01-0.68).

Conclusions: Our findings suggest that inflammation moderates the association between sleep, particularly nighttime wakefulness, and dementia risk. The presence of inflammation may be an important determinant in evaluating how sleep disturbances relate to neurodegeneration.
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http://dx.doi.org/10.1093/sleep/zsaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879417PMC
February 2021

Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy.

EBioMedicine 2020 Jun 5;56:102803. Epub 2020 Jun 5.

Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA.

Background: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment.

Methods: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses.

Findings: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT).

Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.
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http://dx.doi.org/10.1016/j.ebiom.2020.102803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276515PMC
June 2020

Interhemispheric sleep depth coherence predicts driving safety in sleep apnea.

J Sleep Res 2021 04 22;30(2):e13092. Epub 2020 May 22.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Obstructive sleep apnea is associated with increased risk of car crashes; however, conventional measures of sleep apnea severity do not clearly identify those individuals who are at greatest risk. Here we tested whether, among individuals with sleep apnea, those with reduced interhemispheric sleep depth coherence, measured by correlation between right and left hemisphere odds ratio product, are at greater risk. The sample was derived from the Sleep Heart Health Study, a prospective observational cohort study, and included 1,378 adults with sleep apnea. The occurrence of a car crash was ascertained by a questionnaire administered 2 years after the sleep study, which asked about the occurrence of crashes during the year prior to questionnaire administration. We computed the sleep depth coherence from electroencephalograms recorded during baseline sleep studies and after 5 years. The weighted kappa coefficient and Bangdiwala's B were 0.34 and 0.59, respectively, indicating a fair to moderate stability over a 5-year interval. Multivariate logistic regression, adjusted for age, sex, race, body mass index and miles driven per year, was used to assess the risk of a car crash. Compared to the lowest quartile of sleep depth coherence (<0.86), individuals in the highest quartile (>0.93) had a 62% (95% confidence interval, 22%-81%) lower risk of an accident. Further adjustments for usual sleep duration and sleepiness did not meaningfully alter these findings. Higher interhemispheric sleep depth coherence is associated with significantly lower risk of motor vehicle crashes in individuals with sleep apnea. This suggests that high interhemispheric sleep depth coherence may be a marker of resistance to sleep apnea-related adverse neurocognitive outcomes.
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http://dx.doi.org/10.1111/jsr.13092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680278PMC
April 2021

Diagnosis and Management of Obstructive Sleep Apnea: A Review.

JAMA 2020 04;323(14):1389-1400

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Importance: Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA.

Observations: The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events.

Conclusions And Relevance: OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.
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http://dx.doi.org/10.1001/jama.2020.3514DOI Listing
April 2020

An analysis of the relationship between chronic obstructive pulmonary disease, smoking and depression in an integrated healthcare system.

Gen Hosp Psychiatry 2020 May - Jun;64:72-79. Epub 2020 Apr 4.

Veterans Affairs Medical Center, White River Junction, VT, USA; National Center for PTSD, White River Junction, VT, USA; Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH, USA. Electronic address:

Objective: Chronic Obstructive Pulmonary Disease (COPD) and smoking are highly associated with depression and hypoxia. There is limited knowledge about whether hypoxic conditions interact to cause depression.

Method: A population-based cohort study was conducted using the Veterans Affairs (VA) Corporate Data Warehouse. Patients must have accessed any healthcare at a VA facility between 2004 and 2014 and had a negative depression screen (Patient Health Questionnaire-2 (PHQ-2) score ≤ 2). Patients with COPD or a positive depression screen (PHQ-2 score: 3+) during or prior to the year with a negative depression screen were excluded. Logistic regression with annual observations was used to evaluate depression incidence based on COPD and smoking status. Models were adjusted for demographics and other comorbid conditions. A probability scale was used to examine interactions between COPD and smoking.

Results: A total of 3,284,496 patients were included. Patients with COPD and current smokers were at increased risk for developing depression. There were minimal interaction effects between COPD and smoking. The odds of developing depression in a year varied from 1.4% among never smokers without COPD to 2.9.% among current smokers with COPD.

Conclusion: Smoking and COPD are independent risk factors for depression and interact to cause depression. Further research is needed to confirm whether hypoxia contributes to this association.
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http://dx.doi.org/10.1016/j.genhosppsych.2020.03.007DOI Listing
May 2021

Electroconvulsive Therapy in Veterans Health Administration Hospitals: Prevalence, Patterns of Use, and Patient Characteristics.

J ECT 2020 Jun;36(2):130-136

From the Veterans Affairs (VA) Medical Center, White River Junction, VT.

Objectives: The body of large-scale, epidemiological research on electroconvulsive therapy (ECT) in the United States is limited. To address this gap, we assessed demographic, clinical, pharmacological, and mental health treatment history as well as 2-year mortality outcomes associated with ECT use in the largest U.S. health care system.

Methods: Among all patients who sought mental health care at Veterans Health Administration (VHA) hospitals in 2012, we used bivariate analyses to compare patients who did and not receive ECT during 2 years of follow-up. Among the population who received ECT, descriptive statistics were calculated to characterize prior mental health treatment patterns and ECT receipt.

Results: 0.11% (N = 1616) of all VHA mental health patients in 2012 (N = 1,457,053) received ECT in 2 years of follow-up. There was significant regional variation in provision of ECT. Those who received ECT were more likely to have diagnoses of major depressive, bipolar, and personality disorders and were significantly more likely to have had a recent mental health inpatient stay (risk ratio, 6.94). Receipt of ECT was not associated with a difference in all-cause mortality (risk ratio, 0.88). Thirty-two percent of those who received ECT had no substantial antidepressant or therapy trial in the year before index mental health encounter.

Conclusions: Use of ECT in the VHA is rare. Patients who receive ECT have a complex and high-risk profile, not necessarily consistent with the most common indications for ECT.
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http://dx.doi.org/10.1097/YCT.0000000000000635DOI Listing
June 2020

Associations between Medication Assisted Therapy Services Delivery and Mortality in a National Cohort of Veterans with Posttraumatic Stress Disorder and Opioid Use Disorder.

J Dual Diagn 2020 Apr-Jun;16(2):228-238. Epub 2019 Dec 18.

Department of Mental Health, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.

Opioid use disorder (OUD) is a notable concern in the United States (US) and strongly associated with mortality. There is a high prevalence of OUD in patients with posttraumatic stress disorder (PTSD) and the mortality associated with OUD may be exacerbated in patients with PTSD. Medication-assisted treatment (MAT) for OUD has become standard of care for OUD and has been shown to reduce mortality. However, there has been little study of MAT and mortality in patients with PTSD and OUD. We conducted a retrospective cohort study in U.S. veterans who had newly engaged in PTSD treatment, were diagnosed with OUD and were provided MAT for at least one day between 2004 and 2013. We assessed mortality for one year following the index diagnosis date. We calculated all-cause mortality as well as death by external cause, overdose plus suicide, overdose, and suicide rates per 100,000. We used hazard ratios (HR) and 95% confidence intervals (CI) to compare death rates between patients with high versus low adherence to MAT. We evaluated the impact of high versus low exposure to general substance abuse care. We considered a confidence interval that did not cross one to be significant. A total of 5,901 patients met inclusion criteria. Most patients were men and the average age was 43.3 years ( = 13.8). The all-cause mortality rate was 1,370 per 100,000 patients. High adherence to MAT resulted in a non-significant, decreased risk for death due to all-cause (HR = 0.73, 95% CI [0.47, 1.13]), external cause (HR = 0.71, 95% CI [0.38, 1.35]), and overdose or suicide (HR = 0.66, 95% CI [0.33, 1.35]). Patients with high exposure (≥ 60 days) to general substance abuse care were significantly less likely to die due to external cause (HR = 0.39, 95% CI [0.18, 0.85]) and overdose or suicide (HR = 0.31, 95% CI [0.12, 0.77]). In patients with PTSD and OUD, improved adherence to MAT and greater exposure to general substance abuse care may result in lower mortality. Studies with longer follow-up and larger sample sizes to assess the impact of MAT on suicide are needed to confirm our findings.
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http://dx.doi.org/10.1080/15504263.2019.1701218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192001PMC
May 2021

Effects of continuous positive airway pressure on blood pressure in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES).

J Sleep Res 2020 04 14;29(2):e12943. Epub 2019 Nov 14.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Obstructive sleep apnea is associated with hypertension, and short-term studies have demonstrated a modest reduction in blood pressure with continuous positive airway pressure therapy. We evaluated the effects of continuous positive airway pressure versus sham continuous positive airway pressure on blood pressure in 1,101 participants with obstructive sleep apnea from the Apnea Positive Pressure Long-term Efficacy Study, a randomized, sham-controlled double-blinded study designed to assess the impact of continuous positive airway pressure on neurocognition. Participants with apnea-hypopnea index ≥ 10 were randomly assigned to continuous positive airway pressure or sham continuous positive airway pressure. Blood pressures measured in the morning and evening at baseline, 2 months and 6 months were analysed post hoc using a mixed-model repeated-measures analysis of variance. The largest magnitude reduction was approximately 2.4 mmHg in morning systolic pressure that occurred at 2 months in the continuous positive airway pressure arm as compared with an approximate 0.5 mmHg reduction in the sham group (continuous positive airway pressure effect -1.9 mmHg, p = .008). At 6 months, the difference between groups was diminished and no longer statistically significant (continuous positive airway pressure effect -0.9 mmHg, p = .12). Sensitivity analysis with use of multiple imputation approaches to account for missing data did not change the results. Treatment with continuous positive airway pressure for obstructive sleep apnea reduces morning but not evening blood pressure in a population with well-controlled blood pressure. The effect was greater after 2 than after 6 months of treatment.
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http://dx.doi.org/10.1111/jsr.12943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188383PMC
April 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.

Am J Hum Genet 2019 11 24;105(5):1057-1068. Epub 2019 Oct 24.

Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849112PMC
November 2019
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