Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits.

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.

Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 × 10-8). These noncoding variants together significantly contributed to the linkage evidence (P < 10-3). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

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

Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) 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 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S 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 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S 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 AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.

The Epidemiology and Burden of Childhood Chronic Pancreatitis in South Australia.

OBJECTIVE: To assess longitudinal, population-based data on the prevalence and impact of chronic pancreatitis in children. STUDY DESIGN: Administrative data linkage was used to ascertain an index cohort consisting of all individuals who had an initial diagnosis of chronic pancreatitis before age 19 years in the South Australian public hospital system between June 2000 and June 2019. Age- and sex-matched controls were drawn from the general population of South Australia, children with type 1 diabetes, and children with type 2 diabetes. Main outcomes and measures included hospital visits, days in hospital, emergency department (ED) visits, intensive care unit (ICU) admissions, education comparators, and incidence and prevalence estimates. RESULTS: A total of 73 incident cases were identified. The crude prevalence and incidence of pediatric chronic pancreatitis were estimated at 6.8/100 000 and 0.98/100 000 per year, respectively. Of the index cohort, 24 cases (32.8%) of pediatric chronic pancreatitis were identified as occurring in children of Aboriginal and/or Torres Strait Islander descent. Compared with matched general population controls, children with chronic pancreatitis averaged 11-fold more hospital visits, 5-fold more ED visits, and 9-fold more ICU admissions; spent 10-fold more days in the hospital; and had a 2-fold higher rate of absence from school (P < .001 for all). Similarly, children with chronic pancreatitis used substantially more health resources than children with type 1 or 2 diabetes. CONCLUSIONS: Pediatric patients with chronic pancreatitis consume a high volume of public health services and are significantly impacted in their ability to engage in education.

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Definition and diagnosis of cerebral palsy in genetic studies: a systematic review.

AIM: To conduct a systematic review of phenotypic definition and case ascertainment in published genetic studies of cerebral palsy (CP) to inform guidelines for the reporting of such studies. METHOD: Inclusion criteria comprised genetic studies of candidate genes, with CP as the outcome, published between 1990 and 2019 in the PubMed, Embase, and BIOSIS Citation Index databases. RESULTS: Fifty-seven studies met the inclusion criteria. We appraised how CP was defined, the quality of information on case ascertainment, and compliance with international consensus guidelines. Seven studies (12%) were poorly described, 33 studies (58%) gave incomplete information, and 17 studies (30%) were well described. Missing key information precluded determining how many studies complied with the definition by Rosenbaum et al. Only 18 out of 57 studies (32%) were compliant with the Surveillance of Cerebral Palsy in Europe (SCPE) international guidelines on defining CP. INTERPRETATION: Limited compliance with international consensus guidelines on phenotypic definition and mediocre reporting of CP case ascertainment hinders the comparison of results among genetic studies of CP (including meta-analyses), thereby limiting the quality, interpretability, and generalizability of study findings. Compliance with the SCPE guidelines is important for ongoing gene discovery efforts in CP, given the potential for misclassification of unrelated neurological conditions as CP.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

The Canadian Partnership for Tomorrow Project: a pan-Canadian platform for research on chronic disease prevention.

BACKGROUND: Understanding the complex interaction of risk factors that increase the likelihood of developing common diseases is challenging. The Canadian Partnership for Tomorrow Project (CPTP) is a prospective cohort study created as a population-health research platform for assessing the effect of genetics, behaviour, family health history and environment (among other factors) on chronic diseases. METHODS: Volunteer participants were recruited from the general Canadian population for a confederation of 5 regional cohorts. Participants were enrolled in the study and core information obtained using 2 approaches: attendance at a study assessment centre for all study measures (questionnaire, venous blood sample and physical measurements) or completion of the core questionnaire (online or paper), with later collection of other study measures where possible. Physical measurements included height, weight, percentage body fat and blood pressure. Participants consented to passive follow-up through linkage with administrative health databases and active follow-up through recontact. All participant data across the 5 regional cohorts were harmonized. RESULTS: A total of 307 017 participants aged 30-74 from 8 provinces were recruited. More than half provided a venous blood sample and/or other biological sample, and 33% completed physical measurements. A total of 709 harmonized variables were created; almost 25% are available for all participants and 60% for at least 220 000 participants. INTERPRETATION: Primary recruitment for the CPTP is complete, and data and biosamples are available to Canadian and international researchers through a data-access process. The CPTP will support research into how modifiable risk factors, genetics and the environment interact to affect the development of cancer and other chronic diseases, ultimately contributing evidence to reduce the global burden of chronic disease.

The genetics of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a common chronic disease and is associated with high social and economic costs. OSA is heritable, and there is evidence of both direct genetic contributions to OSA susceptibility and indirect contributions via 'intermediate' phenotypes such as obesity, craniofacial structure, neurological control of upper airway muscles and of sleep and circadian rhythm. Investigation of the genetics of OSA is an important research area and may lead to improved understanding of disease aetiology, pathogenesis, adverse health consequences and new preventive strategies and treatments. Genetic studies of OSA have lagged behind other chronic diseases; however recent gene discovery efforts have been successful in finding genetic loci contributing to OSA-associated intermediate phenotypes. Nevertheless, many of the seminal questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This paper reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep apnoea.

Effect of Obstructive Sleep Apnea Treatment on Renal Function in Patients with Cardiovascular Disease.

RATIONALE: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes. OBJECTIVES: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease. METHODS: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit. MEASUREMENTS AND MAIN RESULTS: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m2), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m2/yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings. CONCLUSIONS: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT00738179).

Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity.

BACKGROUND: Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals. RESULTS: We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs. CONCLUSIONS: We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease.

UNLABELLED: Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome-wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population-based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10(-5) was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group-specific component (GC) (odds ratio [OR], 2.54; P = 1.20 × 10(-6)) and lymphocyte cytosolic protein-1 (LCP1) (OR, 3.29; P = 2.96 × 10(-6)). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase-related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 × 10(-6)) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 × 10(-6) ). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). CONCLUSION: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD.

Effectiveness of individual-focused interventions to prevent chronic disease.

BACKGROUND: The burden of chronic disease is projected to assume crisis proportions in most parts of the world by the middle of the century, focusing attention on the need for preventive interventions. We identify and review published research on primary prevention individual-level interventions in current practice and describe and discuss the limitations of the current evidence. The report facilitates prioritizing a research agenda for potential interventions that might be investigated within cohort studies. MATERIALS AND METHODS: This study is a rapid review. Computerized database searches (PubMed and EMBASE) were performed in October 2012 to identify articles on primary prevention interventions that are directed at the individual level. Potentially, relevant International Agency of Research on Cancer handbooks and monographs were also reviewed. The review includes articles reported in English on the efficacy or effectiveness of a preventive intervention in an adult population. It excludes articles on alcohol or tobacco smoking. RESULTS: Many chronic disease interventions directed at individuals report a protective effect in the short term and some evidence for the efficacy of chemoprevention in chronic disease prevention exists. Evidence these effects persist in the longer term is inconsistent. CONCLUSIONS: There are currently only limited evidence-based preventions for most chronic diseases, for which a summary is available in Table A1 (see Appendix B). Most individual-level intervention research studies have been conducted using case-control designs and some small, randomized studies. There are fewer impediments to lifestyle modifications when compared to prevention using chemoprevention and vaccination or other methods of prevention of persistent infection.

Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.

An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10(-20)) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10(-23)). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10(-17)), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Prognostic modeling in early rheumatoid arthritis: reconsidering the predictive role of disease activity scores.

OBJECTIVE: In this prospective cohort study, we provide several prognostic models to predict functional status as measured by the modified Health Assessment Questionnaire (mHAQ). The early adoption of the treat-to-target strategy in this cohort offered a unique opportunity to identify predictive factors using longitudinal data across 20 years. METHODS: A cohort of 397 patients with early RA was used to develop statistical models to predict mHAQ score measured at baseline, 12 months, and 18 months post diagnosis, as well as serially measured mHAQ. Demographic data, clinical measures, autoantibodies, medication use, comorbid conditions, and baseline mHAQ were considered as predictors. RESULTS: The discriminative performance of models was comparable to previous work, with an area under the receiver operator curve ranging from 0.64 to 0.88. The most consistent predictive variable was baseline mHAQ. Patient-reported outcomes including early morning stiffness, tender joint count (TJC), fatigue, pain, and patient global assessment were positively predictive of a higher mHAQ at baseline and longitudinally, as was the physician global assessment and C-reactive protein. When considering future function, a higher TJC predicted persistent disability while a higher swollen joint count predicted functional improvements with treatment. CONCLUSION: In our study of mHAQ prediction in RA patients receiving treat-to-target therapy, patient-reported outcomes were most consistently predictive of function. Patients with high disease activity due predominantly to tenderness scores rather than swelling may benefit from less aggressive treatment escalation and an emphasis on non-pharmacological therapies, allowing for a more personalized approach to treatment. Key Points • Long-term use of the treat-to-target strategy in this patient cohort offers a unique opportunity to develop prognostic models for functional outcomes using extensive longitudinal data. • Patient reported outcomes were more consistent predictors of function than traditional prognostic markers. • Tender joint count and swollen joint count had discordant relationships with future function, adding weight to the possibility that disease activity may better guide treatment when the components are considered separately.

Impact of Transfer Learning Using Local Data on Performance of a Deep Learning Model for Screening Mammography.

Purpose To investigate the issues of generalizability and replication of deep learning models by assessing performance of a screening mammography deep learning system developed at New York University (NYU) on a local Australian dataset. Materials and Methods In this retrospective study, all individuals with biopsy or surgical pathology-proven lesions and age-matched controls were identified from a South Australian public mammography screening program (January 2010 to December 2016). The primary outcome was deep learning system performance-measured with area under the receiver operating characteristic curve (AUC)-in classifying invasive breast cancer or ductal carcinoma in situ (n = 425) versus no malignancy (n = 490) or benign lesions (n = 44). The NYU system, including models without (NYU1) and with (NYU2) heatmaps, was tested in its original form, after training from scratch (without transfer learning), and after retraining with transfer learning. Results The local test set comprised 959 individuals (mean age, 62.5 years ± 8.5 [SD]; all female). The original AUCs for the NYU1 and NYU2 models were 0.83 (95% CI: 0.82, 0.84) and 0.89 (95% CI: 0.88, 0.89), respectively. When NYU1 and NYU2 were applied in their original form to the local test set, the AUCs were 0.76 (95% CI: 0.73, 0.79) and 0.84 (95% CI: 0.82, 0.87), respectively. After local training without transfer learning, the AUCs were 0.66 (95% CI: 0.62, 0.69) and 0.86 (95% CI: 0.84, 0.88). After retraining with transfer learning, the AUCs were 0.82 (95% CI: 0.80, 0.85) and 0.86 (95% CI: 0.84, 0.88). Conclusion A deep learning system developed using a U.S. dataset showed reduced performance when applied "out of the box" to an Australian dataset. Local retraining with transfer learning using available model weights improved model performance. Keywords: Screening Mammography, Convolutional Neural Network (CNN), Deep Learning Algorithms, Breast Cancer Supplemental material is available for this article. © RSNA, 2024 See also commentary by Cadrin-Chênevert in this issue.

Predictions for functional outcome and mortality in acute ischaemic stroke following successful endovascular thrombectomy.

Background: Accurate outcome predictions for patients who had ischaemic stroke with successful reperfusion after endovascular thrombectomy (EVT) may improve patient treatment and care. Our study developed prediction models for key clinical outcomes in patients with successful reperfusion following EVT in an Australian population. Methods: The study included all patients who had ischaemic stroke with occlusion in the proximal anterior cerebral circulation and successful reperfusion post-EVT over a 7-year period. Multivariable logistic regression and Cox regression models, incorporating bootstrap and multiple imputation techniques, were used to identify predictors and develop models for key clinical outcomes: 3-month poor functional status; 30-day, 1-year and 3-year mortality; survival time. Results: A total of 978 patients were included in the analyses. Predictors associated with one or more poor outcomes include: older age (ORs for every 5-year increase: 1.22-1.40), higher premorbid functional modified Rankin Scale (ORs: 1.31-1.75), higher baseline National Institutes of Health Stroke Scale (ORs: 1.05-1.07) score, higher blood glucose (ORs: 1.08-1.19), larger core volume (ORs for every 10 mL increase: 1.10-1.22), pre-EVT thrombolytic therapy (ORs: 0.44-0.56), history of heart failure (outcome: 30-day mortality, OR=1.87), interhospital transfer (ORs: 1.42 to 1.53), non-rural/regional stroke onset (outcome: functional dependency, OR=0.64), longer onset-to-groin puncture time (outcome: 3-year mortality, OR=1.08) and atherosclerosis-caused stroke (outcome: functional dependency, OR=1.68). The models using these predictors demonstrated moderate predictive abilities (area under the receiver operating characteristic curve range: 0.752-0.796). Conclusion: Our models using real-world predictors assessed at hospital admission showed satisfactory performance in predicting poor functional outcomes and short-term and long-term mortality for patients with successful reperfusion following EVT. These can be used to inform EVT treatment provision and consent.

A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome.

BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

High prevalence of undiagnosed obstructive sleep apnoea in the general population and methods for screening for representative controls.

PURPOSE: Undiagnosed obstructive sleep apnoea (OSA) in the community makes comparisons of OSA subjects with control samples from the general population problematic. This study aims to estimate undiagnosed moderate to severe OSA in a general population sample and to determine the capacity of questions from the Berlin questionnaire (BQ) to identify subjects without diagnosed OSA of this severity. METHODS: Using a general population sample (n = 793) with no history of OSA, case and control status for moderate-severe OSA was determined by home-based nasal flow and oximetry-derived apnoea-hypopnoea index using a cut-off value of ≥ 15 events/h to define cases. The diagnostic accuracy of the complete BQ and its component questions in identifying cases was assessed by calculating sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and post-test probabilities. RESULTS: The age-standardised prevalence estimate of moderate-severe OSA was 9.1 % (12.4 % in men, 5.7 % in women). Sensitivity of the BQ in this population was 54 %, and specificity, 70 %. A combination of questions regarding snoring frequency and hypertension provided maximal post-test probability of OSA and greatest post-screen sample size. CONCLUSIONS: Undiagnosed OSA is highly prevalent in the Western Australian general population. While the complete BQ is a sub-optimal screening instrument for the general population, snoring frequency or hypertension can be used to screen out moderate-severe OSA from general population samples with limited reduction in sample size. As there are few general population samples available for epidemiological or genetic studies of OSA and its associated phenotypes, these results may usefully inform future case-control studies.