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In a previous pathway-based, extreme phenotype study, we identified 1064 variants associated with supravalvar aortic stenosis (SVAS) severity in people with Williams syndrome (WS) and either no SVAS or surgical SVAS. Here, we use those variants to develop and test polygenic risk scores (PRS). We used the clumping and thresholding (CT) approach on the full 1064 variants and a 427-variant subset that was part of 13 biologically relevant pathways identified in the previous study. We also used a lasso approach on the full set. We were able to achieve an area under the curve (AUC) of >0.99 for the two CT PRS methods, using only 622 and 320 variants respectively when 2/3 of the initial 217 participants data were used for training and 1/3 for testing. The lasso performed less well. We then evaluated the performance of those PRS variant sets on an additional group of 138 patients with WS with intermediate severity SVAS and found a misclassification rate of <10% between the surgical and intermediate groups, suggesting potential for clinical utility of the score., Competing Interests: Disclosures: The authors report no conflicts.

Background: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent., Methods: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID)., Results: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients., Conclusion: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CAMS serves on advisory boards for Sanofi and Janssen and on speakers' bureaus for Sanofi, Celgene, BMS and Takeda. GJT served as advisor for Novartis. PFY has received payments for lectures from Janssen and Amgen and support for travel expenses from Janssen. RJWK has received support for travel expenses from Novartis and serves on an advisory board of Novartis. PS has received research support from Janssen, Amgen, BMS, Celgene and Karyopharm; and serves on advisory boards for Celgene, Janssen, Amgen, Karyopharm, BMS and Pfizer. NWCJD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, all paid to their institution; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier, all paid to their institution. HMB serves on an advisory board for Pfizer and has received research support from BMS-Celgene, all paid to their institution. DGJC has received payments for lectures for Takeda, and received financial support for travel expenses from Servier, all outside the submitted work. SZ has received research support from Janssen and the Dutch Cancer Society, all paid to their institution; and serves on advisory boards for Janssen, BMS, Oncopeptides, and Sanofi, all paid to their institution. Others: All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)