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Atypical diabetes with overlapping clinical features of type 1 (T1D) and type 2 (T2D) is common and challenging diagnostically and for implementing effective treatment. Here, we validate a recently reported genetic probability of type 1 diabetes (GenProb‐T1D) from the UK Biobank (UKB) for differentiating type 1 diabetes and type 2 diabetes in a diabetes patient cohort from a healthcare system‐based biobank in the USA. Among 3,363 diabetes patients, we confirmed the performance of GenProb‐T1D in differentiating typical type 1 diabetes vs type 2 diabetes. Furthermore, for 359 atypical diabetes patients, those with GenProb‐T1D higher than the pre‐defined cutoff derived from the UKB had clinical presentations more consistent with that of typical type 1 diabetes. Similar findings were found in participants of European and non‐European ancestries. This study provides necessary validation to translate GenProb‐T1D into genetic testing in a multi‐ancestry cohort. Measuring underlying genetic susceptibility of type 1 diabetes and type 2 diabetes can supplement current clinical tools for earlier and more accurate diagnoses of diabetes. [ABSTRACT FROM AUTHOR]

This paper proposes an approach of H ∞ /generalized H 2 (GH 2) static output feedback control for vehicle active suspension. To address the conflicting performance requirements in active suspension, the H ∞ norm is minimized to optimize the ride comfort performance, while the GH 2 norm is designed to meet time-domain hard constraints, including suspension stroke, road-holding performance, and actuator saturation. As not all states of active suspension are measurable in practice, the static output feedback control is designed using suspension stroke and sprung mass velocity as feedback signals. An invertible matrix condition is introduced in the static output feedback control design, which transforms the control problem into a convex optimization problem that can be solved using linear matrix inequalities (LMIs). Simulation and hardware-in-the-loop (HiL) experiments are conducted on both bump and random road responses for active and passive suspension of a 2-degree-of-freedom quarter vehicle. The proposed active suspension H ∞ / GH 2 static output feedback controller is compared with H ∞ state feedback controller and the existing controller solved by LMIs and genetic algorithms (GAs), demonstrating that the proposed strategy achieves better ride comfort performance under various road conditions while satisfying all time-domain hard constraints. [ABSTRACT FROM AUTHOR]

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD −0.04, P = 9.6 × 10−7, and −8.45 μU/mg, P = 5.6 × 10−6, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD −4.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function. Article Highlights: Process-specific genetic scores (partitioned polygenic scores [pPS]) help explain clinical heterogeneity in type 2 diabetes, but whether they inform differential response to diabetes prevention strategies is unknown. In the Diabetes Prevention Program clinical trial, we examined pPS for associations with longitudinal glycemic measures and type 2 diabetes development. Higher β-cell pPS was associated with reduced baseline and even further reduced 1-year β-cell function despite diabetes prevention interventions. Diabetes prevention interventions may not optimally prevent β-cell function decline in people with genetic susceptibility for β-cell dysfunction, which may contribute to the heterogeneity seen in progression of diabetes development. [ABSTRACT FROM AUTHOR]

Context Misclassification of diabetes type occurs in people with atypical presentations of type 1 diabetes (T1D) or type 2 diabetes (T2D). Although current clinical guidelines suggest clinical variables and treatment response as ways to help differentiate diabetes type, they remain insufficient for people with atypical presentations. Objective This work aimed to assess the clinical utility of 2 polygenic scores (PGSs) in differentiating between T1D and T2D. Methods Patients diagnosed with diabetes in the UK Biobank were studied (N = 41 787), including 464 (1%) and 15 923 (38%) who met the criteria for classic T1D and T2D, respectively, and 25 400 (61%) atypical diabetes. The validity of 2 published PGSs for T1D (PGST1D) and T2D (PGST2D) in differentiating classic T1D or T2D was assessed using C statistic. The utility of genetic probability for T1D based on PGSs (GenProb-T1D) was evaluated in atypical diabetes patients. Results The joint performance of PGST1D and PGST2D for differentiating classic T1D or T2D was outstanding (C statistic = 0.91), significantly higher than that of PGST1D alone (0.88) and PGST2D alone (0.70), both P less than.001. Using an optimal cutoff of GenProb-T1D, 23% of patients with atypical diabetes had a higher probability of T1D and its validity was independently supported by clinical presentations that are characteristic of T1D. Conclusion PGST1D and PGST2D can be used to discriminate classic T1D and T2D and have potential clinical utility for differentiating these 2 types of diseases among patients with atypical diabetes. [ABSTRACT FROM AUTHOR]

In a large population-based cohort, we show not all heterozygous APOEɛ4 carriers are at increased risk for Alzheimer's disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS. [ABSTRACT FROM AUTHOR]