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An important issue in the analysis of rare variant association studies is the ability to annotate nonsynonymous variants in terms of their likely importance as affecting protein function. To address this, AlphaMissense was recently released and was shown to have good performance using benchmarks based on variants causing severe disease and on functional assays. Here, we assess the performance of AlphaMissense across 18 genes which had previously demonstrated association between rare coding variants and hyperlipidaemia, hypertension or type 2 diabetes. The strength of evidence in favour of association, expressed as the signed log p value (SLP), was compared between AlphaMissense and 43 other annotation methods. The results demonstrated marked variability between genes regarding the extent to which nonsynonymous variants contributed to evidence for association and also between the performance of different methods of annotating the nonsynonymous variants. Although AlphaMissense produced the highest SLP on average across genes, it produced the maximum SLP for only 4 genes. For some genes, other methods produced a considerably higher SLP and there were examples of genes where AlphaMissense produced no evidence for association while another method performed well. The marked inconsistency across genes means that it is difficult to decide on an optimal method of analysis of sequence data. The fact that different methods perform well for different genes suggests that if one wished to use sequence data for individual risk prediction then gene-specific annotation methods should be used.
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Mental health disorders have become a global problem, garnering considerable attention. However, the root causes of deteriorating mental health remain poorly understood, with existing literature predominantly concentrating on socioeconomic conditions and psychological factors. This study uses multi-linear and geographically weighted regressions (GWR) to examine the associations between built and natural environmental attributes and the prevalence of depression in US counties. The findings reveal that job sprawl and land mixed use are highly correlated with a lower risk of depression. Additionally, the presence of green spaces, especially in urban area, is associated with improved mental health. Conversely, higher concentrations of air pollutants, such as PM2.5 and CO, along with increased precipitation, are linked to elevated depression rates. When considering spatial correlation through GWR, the impact of population density and social capital on mental health displays substantial spatial heterogeneity. Further analysis, focused on two high depression risk clustering regions (northwestern and southeastern counties), reveals nuanced determinants. In northwestern counties, depression rates are more influenced by factors like precipitation and socioeconomic conditions, including unemployment and income segregation. In southeastern counties, population demographic characteristics, particularly racial composition, are associated with high depression prevalence, followed by built environment factors. Interestingly, job growth and crime rates only emerge as significant factors in the context of high depression risks in southeastern counties. This study underscores the robust linkages and spatial variations between built and natural environments and mental health, emphasizing the need for effective depression treatment to incorporate these multifaceted factors.
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ABSTRACT: With advances in sequencing, individuals with clonal hematopoiesis of indeterminate potential (CHIP) are increasingly being identified, making it essential to understand its prognostic implications. We conducted a systematic review of studies comparing the risk of clinical outcomes in individuals with and without CHIP. We searched MEDLINE and EMBASE and included original research reporting an outcome risk measure in individuals with CHIP, adjusted for the effect of age. From the 3305 studies screened, we included 88 studies with 45 to 470 960 participants. Most studies had a low-to-moderate risk of bias in all domains of the Quality in Prognostic Factor Studies tool. Random-effects meta-analyses were performed for outcomes reported in at least 3 studies. CHIP conferred an increased risk of all-cause mortality (hazard ratio [HR], 1.34; 95% confidence interval, 1.19-1.50), cancer mortality (HR, 1.46; 1.13-1.88), composite cardiovascular events (HR, 1.40; 1.19-1.65), coronary heart disease (HR, 1.76; 1.27-2.44), stroke (HR, 1.16; 1.05-1.28), heart failure (HR, 1.27; 1.15-1.41), hematologic malignancy (HR, 4.28; 2.29-7.98), lung cancer (HR, 1.40; 1.27-1.54), renal impairment (HR, 1.25; 1.18-1.33) and severe COVID-19 (odds ratio [OR], 1.46; 1.18-1.80). CHIP was not associated with cardiovascular mortality (HR, 1.09; 0.97-1.22), except in the subgroup analysis restricted to larger clones (HR, 1.31; 1.12-1.54). Isolated DNMT3A mutations did not increase the risk of myeloid malignancy, all-cause mortality, or renal impairment. The reasons for heterogeneity between studies included differences in definitions and measurements of CHIP and the outcomes, and populations studied. In summary, CHIP is associated with diverse clinical outcomes, with clone size, specific gene, and inherent patient characteristics important mediators of risk.
Subject(s)
Clonal Hematopoiesis , Humans , Prognosis , DNA Methyltransferase 3A , Mutation , COVID-19/mortality , COVID-19/geneticsABSTRACT
INTRODUCTION: This longitudinal study was based on the outcomes of Donor Lymphocyte Infusion (DLI) for falling peripheral blood (PB) CD34+ and CD3+ donor chimerism (DC). METHODS: From 2012 to 2018, data was collected from the BMT database and electronic medical records (EMR). The primary objective was to compare the indication for DLI based on falling PB CD34+ or CD3+ DC in patients post allo-SCT for AML and MDS and their overall survival (OS). RESULTS: 18/70 patients met the inclusion criteria. Indications for DLI were i) falling PB CD34+ DCâ¯≤â¯80â¯% with morphological relapse, ii) falling PB CD34+ DCâ¯≤â¯80â¯% without morphological relapse and iii) falling PB CD3+ DCâ¯≤â¯80â¯% without falling PB CD34+ DC. Log rank analysis showed falling PB CD34+ DC and morphological relapse had significantly lower OS. Linear regression demonstrated better OS post DLI if there was PB CD34+ and CD3+ chimerism response at 30 days (pâ¯=â¯0.029), GVHD (pâ¯=â¯0.032) and tapering immunosuppression at the time of falling DC (pâ¯=â¯0.042). CONCLUSION: DLI for PB CD34+ DC valuesâ¯≤â¯80â¯% and morphological relapse had the lowest OS. In this study, full DC was achieved after DLI even with a PB CD3+DC value as low as 13â¯%, provided the PB CD34+ DC remained >â¯80â¯%. Further research is vital in CD34+ DC as a biomarker for disease relapse and loss of engraftment.
Subject(s)
Antigens, CD34 , Leukemia, Myeloid, Acute , Lymphocyte Transfusion , Myelodysplastic Syndromes , Transplantation, Homologous , Humans , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/mortality , Male , Female , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/immunology , Middle Aged , Retrospective Studies , Adult , Longitudinal Studies , Antigens, CD34/analysis , Aged , Hematopoietic Stem Cell Transplantation/methods , CD3 Complex/analysis , Transplantation Chimera , Young Adult , Tissue Donors , Graft vs Host Disease/etiology , Graft vs Host Disease/diagnosisABSTRACT
A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 5 , Biological Specimen Banks , Exome Sequencing , Genetic Predisposition to Disease , Hyperlipidemias , Receptors, LDL , Humans , Hyperlipidemias/genetics , United Kingdom/epidemiology , Receptors, LDL/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , Proprotein Convertase 9/genetics , Exome/genetics , Genetic Variation , Angiopoietin-Like Protein 3 , Female , Male , UK Biobank , Lipoproteins , Apolipoprotein C-IIIABSTRACT
Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4-CD8-CD25+CD44-) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle-restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7+CD1a- thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.
Subject(s)
Adaptor Proteins, Signal Transducing , LIM Domain Proteins , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , T-Cell Acute Lymphocytic Leukemia Protein 1 , Animals , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , T-Cell Acute Lymphocytic Leukemia Protein 1/metabolism , T-Cell Acute Lymphocytic Leukemia Protein 1/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , LIM Domain Proteins/metabolism , LIM Domain Proteins/genetics , Thymus Gland/metabolism , Thymus Gland/pathology , Humans , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathologySubject(s)
DNA-Binding Proteins , Dioxygenases , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Proto-Oncogene Proteins , Humans , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Genes, Tumor SuppressorABSTRACT
Background: Digital health studies using electronic patient reported outcomes (ePROs), wearables, and clinical data to provide a more comprehensive picture of patient health. Methods: Newly initiated patients on upadacitinib or adalimumab for RA will be recruited from community settings in the Excellence NEtwork in RheumatoloGY (ENRGY) practice-based research network. Over the period of three to six months, three streams of data will be collected (1) linkable physician-derived data; (2) self-reported daily and weekly ePROs through the ArthritisPower registry app; and (3) biometric sensor data passively collected via wearable. These data will be analyzed to evaluate correlations among the three types of data and patient improvement on the newly initiated medication. Conclusions: Results from this study will provide valuable information regarding the relationships between physician data, wearable data, and ePROs in patients newly initiating an RA treatment, and demonstrate the feasibility of digital data capture for Remote Patient Monitoring of patients with rheumatic disease.
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INTRODUCTION: Previous studies have demonstrated effects of rare coding variants on common, clinically relevant phenotypes although the additive burden of these variants makes only a small contribution to overall trait variance. Although recessive effects of individual homozygous variants have been studied, little work has been done to elucidate the impact of rare coding variants occurring together as compound heterozygotes. METHODS: In this study, attempts were made to identify pairs of variants likely to be occurring as compound heterozygotes using 200,000 exome-sequenced subjects from the UK Biobank. Pairs of variants, which were seen together in the same subject more often than would be expected by chance, were excluded as it was assumed that these might be present in the same haplotype. Attention was restricted to variants with minor allele frequency ≤0.05 and to those predicted to alter amino acid sequence or prevent normal gene expression. For each gene, compound heterozygotes were assigned scores based on the rarity and predicted functional consequences of the constituent variants and the scores were used in a logistic regression analysis to test for association with hypertension, hyperlipidaemia, and type 2 diabetes. RESULTS: No statistically significant associations were observed and the results conformed to the distribution, which would be expected under the null hypothesis. The average number of apparently compound heterozygous subjects for each gene was only 282.2. CONCLUSION: It seems difficult to detect an effect of compound heterozygotes on the risk of these phenotypes. Even if recessive effects from compound heterozygotes do occur, they would only affect a small number of people and overall would not make a substantial contribution to phenotypic variance. This research has been conducted using the UK Biobank Resource.
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Exome , Phenotype , Female , Humans , Male , Diabetes Mellitus, Type 2/genetics , Exome/genetics , Exome Sequencing/methods , Gene Frequency/genetics , Genes, Recessive , Genetic Predisposition to Disease , Genetic Variation , Heterozygote , UK Biobank , United KingdomABSTRACT
Background: Genetic variants causing diseases with hypertension as a secondary feature have previously been identified. Studies focussing on primary hypertension have utilised common and latterly rare genetic variants in attempts to elucidate the genetic contribution to the risk of primary hypertension. Summary: Using genome-wide association studies (GWASs), associations of hypertension with hundreds of common genetic variants have been reported, implicating thousands of genes. Individual variants have small effect sizes and cumulatively account for around 6% of genetic risk. The common variant signal is enriched for relevant tissues and physiological processes, while some variants are associated with traits expected to have secondary impacts on hypertension risk, such as fruit intake, BMI, or time watching television. Studies using rare variants obtained from exome sequence data have implicated a small number of genes for which impaired function has moderate effects on blood pressure and/or hypertension risk. Notably, genetic variants which impair elements of guanylate cyclase activation, stimulated by either natriuretic hormones or nitric oxide, increase hypertension risk. Conversely, variants impairing dopamine beta-hydroxylase or renin production are associated with lower blood pressure. Variants for which a definite effect can be designated remain cumulatively extremely rare and again make only a small contribution to overall genetic risk. Although these results are of interest, it is not clear that they provide radical new insights or identify drug targets which were not previously known. Nor does it seem that genetic testing could be useful in terms of quantifying disease risk or guiding treatment. Key Messages: Research has increased our knowledge about the relationship between naturally occurring genetic variation and risk of hypertension. Although some results serve to confirm our understanding of underlying physiology, their value in terms of potentially leading to practical advances in the management of hypertension appears questionable.
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OBJECTIVES: To compare the detection rate of clinically significant prostate cancer (csPC) and prostate cancer (PC) and to find out the diagnostic concordance between microultrasound (mUS), a high-resolution imaging system that can identify suspicious prostate lesions and biopsy them in real time, and multiparametric magnetic resonance imaging (mpMRI)-guided prostate fusion biopsies. METHODS: A prospective, multicenter, single-blind, single cohort study was conducted involving 80 patients with clinically suspected PC who underwent concomitant mpMRI-guided fusion prostate biopsy (Koelis System) and mUS-guided biopsy (ExactVu System) RESULTS: The detection rate of csPC was slightly higher for image-guided fusion biopsy (21.25% vs 18.75%), but this difference was not statistically significant (Pâ¯=â¯.453). There was also no significant difference in overall PC diagnosis (50% vs 51.25%, Pâ¯=â¯.897). The degree of agreement between the 2 diagnostic techniques for the detection of csPC as assessed by Cohen's Kappa concordance index was satisfactory κ Ìâ¯=â¯0.676. The degree of International Society of Urological Pathology of targeted biopsies obtained from concordant lesions was also represented by satisfactory concordance with a Kappa index of κ Ìâ¯=â¯0. 696. CONCLUSION: mUS-guided biopsy is presented as an effective diagnostic method for the diagnosis of csPC compared to image-guided fusion biopsy. No differences are found in the detection rates of csPC and PC between the 2 strategies and satisfactory concordance is found in terms of histopathological findings.
Subject(s)
Prostate , Prostatic Neoplasms , Humans , Male , Biopsy , Cohort Studies , Image-Guided Biopsy/methods , Magnetic Resonance Imaging/methods , Prospective Studies , Prostate/diagnostic imaging , Prostate/pathology , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Single-Blind MethodABSTRACT
OBJECTIVE: To describe blood pressure and glycemic control by racial/ethnic group in the US Community Health Center (CHC) patient population, and whether center characteristics, proxying for higher resource levels and better quality of care, were associated with greater rates of controlled cardiometabolic conditions. METHODS: Data came from the Uniform Data System, representing aggregate patient clinical data for individual health centers in 2019. Descriptive analyses were conducted weighting by health center patient populations to produce race-specific national rates of blood pressure and glycemic control, and linear regression is used to test whether cardiometabolic control rates varied by center characteristics. RESULTS: Hypertension was controlled for 67.2% of non-Hispanic White, 66.9% of Hispanic, and 56.7% of non-Hispanic Black patients. Diabetes was controlled for 70.7% of non-Hispanic White, 65.7% of Hispanic, and 66.1% of non-Hispanic Black patients. The rate of blood pressure control was 2.54 to 3.99 percentage points higher across racial/ethnic groups in health centers that adopted a patient-centered medical home (PCMH) model of care relative to non-PCMH centers, while glycemic control was 1.08 to 2.27 pp. higher as a function of PCMH certification. Results for other center characteristics did not show consistent patterns across racial groups or outcomes. CONCLUSION: This study documented racial and ethnic health disparities in the CHC patient population after major expansion of the CHC program. CHCs with PCMH certification have improved clinical outcomes among patients with hypertension and diabetes across racial/ethnic groups relative to centers without this certification.
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Diabetes Mellitus , Hypertension , Humans , Blood Pressure , Glycemic Control , Community Health Centers , Hypertension/epidemiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/therapyABSTRACT
We develop county-level measures of structural and institutional barriers to care, and test associations between these barriers and birth outcomes for US-born Black and White mothers using national birth records for 2014-2017. Results indicate elevated odds of greater preterm birth severity for Black mothers in counties with higher uninsurance rates among Black adults, fewer Black physicians per Black residents, and fewer publicly-funded contraceptive services. Most structural barriers were not associated with small-for-gestational-age birth, and barriers defined for Black residents were not associated with birth outcomes for White mothers, with the exception of Black uninsurance rate. Structural determinants of care may influence preterm birth risk for Black Americans.
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Infant, Small for Gestational Age , Premature Birth , Adult , Female , Humans , Infant, Newborn , Delivery of Health Care , Premature Birth/epidemiology , Risk Factors , White , Black or African American , Medically UninsuredABSTRACT
There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow-derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.
Subject(s)
Cytomegalovirus Infections , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Peripheral Blood Stem Cell Transplantation , Humans , Aged , New Zealand/epidemiology , Peripheral Blood Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/epidemiology , Graft vs Host Disease/prevention & control , Myelodysplastic Syndromes/therapy , RecurrenceABSTRACT
Socially disadvantaged groups generally are more likely to reside in areas with less desirable conditions. We examined longitudinal relationships between neighborhood resident characteristics and amenities from 1990 to 2010 in an urban area of Utah, U.S. Four temporal patterns of social inequities are described using mixed-effects models: historical inequities; differential selection into amenity-rich tracts; differential investment in amenities; and simultaneous twenty-year change. Results indicate historical differences by neighborhood socioeconomic status, with lower status tracts having fewer green/natural amenities and higher air pollution in 1990 but also greater walkability and more food stores. Differences in amenities by neighborhood socioeconomic status widened over time as aggregate socioeconomic status disproportionately increased in tracts with more green/natural amenities, less air pollution, and lower walkability in 1990, consistent with differential selection. Tract percentage non-Hispanic White did not predict historical differences, but tracts that were less walkable and had fewer healthy food stores in 1990 experienced larger subsequent increases in racial/ethnic diversity. Tracts with higher relative to lower percentage non-Hispanic White in 1990 had larger decreases in air pollution but declining green/natural amenities. This study shows how social inequities in neighborhood amenities change over time, providing evidence of historical socioeconomic differences increasing from differential resident selection.
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Introduction: A previous study of 200,000 exome-sequenced UK Biobank participants to test for association of rare coding variants with hypertension implicated two genes at exome-wide significance, DNMT3A and FES. A total of 42 genes had an uncorrected p value <0.001. These results were followed up in a larger sample of 470,000 exome-sequenced participants. Methods: Weighted burden analysis of rare coding variants in a new sample of 97,050 cases and 172,263 controls was carried out for these 42 genes. Those showing evidence for association were then analysed in the combined sample of 167,127 cases and 302,691 controls. Results: The association of DNMT3A and FES with hypertension was replicated in the new sample and they and the previously implicated gene NPR1, which codes for a membrane-bound guanylate cyclase, were all exome-wide significant in the combined sample. Also exome-wide significant as risk genes for hypertension were GUCY1A1, ASXL1, and SMAD6, while GUCY1B1 had a nominal p value of <0.0001. GUCY1A1 and GUCY1B1 code for subunits of a soluble guanylate cyclase. For two genes, DBH, which codes for dopamine beta hydroxylase, and INPPL1, rare coding variants predicted to impair gene function were protective against hypertension, again with exome-wide significance. Conclusion: The findings offer new insights into biological risk factors for hypertension which could be the subject of further investigation. In particular, genetic variants predicted to impair the function of either membrane-bound guanylate cyclase, activated by natriuretic peptides, or soluble guanylate cyclase, activated by nitric oxide, increase risk of hypertension. Conversely, variants impairing the function of dopamine beta hydroxylase, responsible for the synthesis of norepinephrine, reduce hypertension risk.
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BACKGROUND: Digital health studies using electronic patient-reported outcomes (ePROs) and wearables bring new challenges, including the need for participants to consistently provide trial data. OBJECTIVE: This study aims to characterize the engagement, protocol adherence, and data completeness among participants with rheumatoid arthritis enrolled in the Digital Tracking of Arthritis Longitudinally (DIGITAL) study. METHODS: Participants were invited to participate in this app-based study, which included a 14-day run-in and an 84-day main study. In the run-in period, data were collected via the ArthritisPower mobile app to increase app familiarity and identify the individuals who were motivated to participate. Successful completers of the run-in period were mailed a wearable smartwatch, and automated and manual prompts were sent to participants, reminding them to complete app input or regularly wear and synchronize devices, respectively, during the main study. Study coordinators monitored participant data and contacted participants via email, SMS text messaging, and phone to resolve adherence issues per a priori rules, in which consecutive spans of missing data triggered participant contact. Adherence to data collection during the main study period was defined as providing requested data for >70% of 84 days (daily ePRO, ≥80% daily smartwatch data) or at least 9 of 12 weeks (weekly ePRO). RESULTS: Of the 470 participants expressing initial interest, 278 (59.1%) completed the run-in period and qualified for the main study. Over the 12-week main study period, 87.4% (243/278) of participants met the definition of adherence to protocol-specified data collection for weekly ePRO, and 57.2% (159/278) did so for daily ePRO. For smartwatch data, 81.7% (227/278) of the participants adhered to the protocol-specified data collection. In total, 52.9% (147/278) of the participants met composite adherence. CONCLUSIONS: Compared with other digital health rheumatoid arthritis studies, a short run-in period appears useful for identifying participants likely to engage in a study that collects data via a mobile app and wearables and gives participants time to acclimate to study requirements. Automated or manual prompts (ie, "It's time to sync your smartwatch") may be necessary to optimize adherence. Adherence varies by data collection type (eg, ePRO vs smartwatch data). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/14665.