Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean.

Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic yield was highest in patients referred for seizures and developmental delay/intellectual disability. The genetic diagnosis had an impact on clinical management in 52% of patients. Referrals to other health professionals and changes in therapy were the most frequently reported clinical consequences. In conclusion, despite limited financial resources, our genetics service resulted in a reasonably high molecular diagnostic yield. Even in this resource-limited setting, a genetic diagnosis had an impact on clinical management for the majority of patients. Our approach with a visiting clinical geneticist may be an example for others who are developing genetic services in similar settings.

The use of corticosteroids does not influence CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency.

Corticosteroids inhibit HIV-related immune activation and seem to have a mild favorable effect on immunological recovery in patients with CD4+ counts ≥200 cells/mm3. Data in patients with advanced immunodeficiency are lacking. We analyzed whether corticosteroids negatively influence the short-term CD4+ lymphocyte recovery in patients with CD4+ cell counts <200 cells/mm3 started on combination antiretroviral therapy (cART). We performed a retrospective cohort analysis including all HIV-infected patients under follow-up in our hospital with a documented episode of Pneumocystis Jirovecii Pneumonia (PJP) in the cART era. CD4+ lymphocyte recovery was assessed at three months after the episode of PJP and subsequent start of cART, comparing patients that received adjunctive corticosteroids (AC) versus patients that did not receive corticosteroids (standard care (SC)). In total, 66 patients with an episode of PJP were identified with 38 patients in the AC-group versus 28 patients in the SC-group. Almost all baseline characteristics were similar, including mean CD4+ lymphocyte counts. After three months, the mean CD4+ cell count did not differ; 222 cells/mm3 for the SC-group versus 259 cells/mm3 for the AC-group (p = .29). The use of corticosteroids does not alter CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency in the first months of antiretroviral therapy.

Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial.

AIMS: Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease. METHODS AND RESULTS: Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months). CONCLUSION: There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.

Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability.

PURPOSE: This study investigated whole-exome sequencing (WES) yield in a subset of intellectually disabled patients referred to our clinical diagnostic center and calculated the total costs of these patients' diagnostic trajectory in order to evaluate early WES implementation. METHODS: We compared 17 patients' trio-WES yield with the retrospective costs of diagnostic procedures by comprehensively examining patient records and collecting resource use information for each patient, beginning with patient admittance and concluding with WES initiation. We calculated cost savings using scenario analyses to evaluate the costs replaced by WES when used as a first diagnostic tool. RESULTS: WES resulted in diagnostically useful outcomes in 29.4% of patients. The entire traditional diagnostic trajectory average cost was $16,409 per patient, substantially higher than the $3,972 trio-WES cost. WES resulted in average cost savings of $3,547 for genetic and metabolic investigations in diagnosed patients and $1,727 for genetic investigations in undiagnosed patients. CONCLUSION: The increased causal variant detection yield by WES and the relatively high costs of the entire traditional diagnostic trajectory suggest that early implementation of WES is a relevant and cost-efficient option in patient diagnostics. This information is crucial for centers considering implementation of WES and serves as input for future value-based research into diagnostics.Genet Med 18 9, 949-956.

Prediction of individual lifetime cardiovascular risk and potential treatment benefit: development and recalibration of the LIFE-CVD2 model to four European risk regions.

AIMS: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals. METHODS AND RESULTS: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region. CONCLUSION: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines.

The study introduces LIFE-CVD2, a new tool that helps predict the risk of heart disease over a person's lifetime, and highlights how where you live in Europe can affect this risk.Using health information from over 687 000 people, LIFE-CVD2 looks at things like blood pressure and whether someone smokes to figure out their chance of having heart problems later in life. Health information from another 1.6 million people in seven different European countries was used to show that it did a good job of predicting who might develop heart disease.Knowing your heart disease risk over your whole life helps doctors give you the best advice to keep your heart healthy. Let us say there is a 50-year-old woman who smokes and has a bit high blood pressure. Right now, she might not look like she is in danger. But with the LIFE-CVD2 tool, doctors can show her how making changes today, like lowering her blood pressure or stopping smoking, could mean many more years without heart problems. These healthy changes can make a big difference over many years.

Impact of a Patient's Baseline Risk on the Relative Benefit and Harm of a Preventive Treatment Strategy: Applying Trial Results in Clinical Decision Making.

Background For translating an overall trial result into an individual patient's expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field-Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (P=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE-LY trial (P=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE-LY trial (P<0.001) for major bleeding. Quartile-specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26-0.61) to 1.04 (95% CI, 0.83-1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42-0.88) to 1.20 (95% CI, 0.97-1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Heterogeneity of Treatment Effects From an Intensive Lifestyle Weight Loss Intervention on Cardiovascular Events in Patients With Type 2 Diabetes: Data From the Look AHEAD Trial.

OBJECTIVE: To explore the presence of heterogeneity of treatment effect (HTE) of an intensive lifestyle intervention on the occurrence of major cardiovascular events (MACE) in overweight or obese patients with type 2 diabetes, and to identify patient characteristics associated with individual treatment effect. RESEARCH DESIGN AND METHODS: In 4,901 participants from the Action for Health in Diabetes (Look AHEAD) trial, a penalized Cox regression model to predict treatment effect of intensive lifestyle intervention for the risk of MACE was derived, including all possible treatment-by-covariate interaction terms. The ability of the model to predict HTE was confirmed by calculating hazard ratios (HRs) and absolute risk change in quartiles of predicted treatment effect, and baseline patient characteristics were compared between quartiles. RESULTS: In quartile 1 of predicted treatment effect, with the highest predicted risk reduction, there was a significant treatment benefit of intensive lifestyle intervention (HR 0.64 [95% CI 0.49-0.83]), whereas there was no effect from treatment in quartiles 2 and 3 (HR 0.81 [95% CI 0.58-1.14] and 1.13 [95% CI 0.80-1.60], respectively) and a detrimental effect in quartile 4 (HR 1.37 [95% CI 1.09-1.73]). Several patient characteristics in demographics, medical history, physical examination, and laboratory values were associated with the level of treatment effect. CONCLUSIONS: This post hoc analysis of the Look AHEAD trial showed that an intensive lifestyle intervention aimed at weight loss may reduce cardiovascular events in selected patients but may have a detrimental treatment effect in others.

Normal-range thyroid-stimulating hormone levels and cardiovascular events and mortality in type 2 diabetes.

AIMS: Thyroid dysfunction is a risk factor for cardiovascular disease. Whether thyroid function within the normal range is a risk factor for cardiovascular disease remains uncertain. The aim of this study is to evaluate whether plasma thyroid-stimulating hormone (TSH) levels in the normal range are a risk factor for cardiovascular disease and mortality in participants with type 2 diabetes mellitus with high cardiovascular risk. METHODS: We included 1265 participants with high cardiovascular risk, type 2 diabetes, and TSH within the normal range (0.35-5.00 mIU/L) from the Second Manifestations of ARTerial disease cohort. The primary outcome was major cardiovascular events (MACE; vascular death, stroke and myocardial infarction). Secondary outcomes of interest were the separate vascular outcomes and all-cause mortality. Cox proportional hazard models were used to evaluate the risk of plasma TSH levels on all outcomes. RESULTS: A total of 191 MACE occurred during a total follow-up of 8183 years. Plasma TSH levels were not associated with MACE (hazard ratio (HR) per mIU/L TSH increase 0.93; 95% confidence interval (95%CI) 0.80-1.08). With a total of 54 strokes during the study period, plasma TSH was associated with a lower risk of stroke (HR per mIU/L 0.64, 95% CI 0.45-0.89). There was no association between plasma TSH levels and risk of myocardial infarction, vascular death, or all-cause mortality. CONCLUSIONS: Higher TSH levels within the normal range are associated with a lower risk of stroke in high-risk patients with type 2 diabetes, but not associated with the risk of other cardiovascular events or mortality.

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.

Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.

Ciliary disturbances in syndromal and non-syndromal obesity.

Obesity is an increasing global health problem. Although it is mainly thought to be due to the changing obesogenic environment, the genetic contribution has been estimated between 40-70%. A number of genes have been identified that cause obesity in animals as well as in humans. Rare highly penetrant monogenic forms of obesity can cause both syndromal and non-syndromal forms of obesity. Bardet-Biedl syndrome and Alström syndrome are well known monogenic obesity syndromes caused by primary cilia defects. The pathogenesis of the obesity phenotype in these disorders is however not fully understood. Disturbance of the appetite regulation system, abnormalities in body composition and decreased energy expenditure have been suggested to cause obesity in these ciliopathies. There are currently 19 known genes associated with Bardet-Biedl syndrome and one Alström syndrome gene. Although ciliopathy genes have been described primarily in these syndromal obesity disorders, non-syndromal obesity may also result from disturbed cilia function. There are multiple genes associated with both obesity and ciliary function. Here we provide an overview of the current knowledge of the clinical, pathophysiological and genetic aspects of obesity in patients with ciliary defects.