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PubMed2026

Large-scale multi-omics enhance risk prediction for type 2 diabetes.

BACKGROUND: Polygenic risk scores (PRS), metabolomics, and proteomics have each shown promise in improving type 2 diabetes risk prediction, but their combined utility beyond established clinical models remains unclear. We aimed to evaluate whether integrating multi-omics biomarkers enhances 10-year type 2 diabetes risk prediction beyond single-omics extensions and the clinical Cambridge Diabetes Risk Score (CDRS), which includes HbA1c measurements. METHODS: We analysed data from 42,840 UK Biobank participants without diagnosed diabetes at baseline. The study population was split into a derivation set (Phase 1 metabolomics release, N = 23,108) to fit models and an independent validation set (Phase 2 release, N = 19,732) to evaluate performance. Data for a PRS for type 2 diabetes, 11 metabolites, and 15 proteins were added to the CDRS to develop multi-omics prediction models. Model performance was evaluated using Harrell's C-index and the net reclassification index (NRI). RESULTS: During 10 years of follow-up, 1090 participants developed incident type 2 diabetes. Among individual omics layers, proteomics contributed the greatest improvement in predictive performance, increasing the C-index from 0.862 (clinical CDRS) to 0.884 (ΔC-index; + 0.022; P < 0.001), with a continuous NRI of 42.0%. The full multi-omics model further significantly increased the C-index compared to a model combining the clinical CDRS with proteomics data (C-index, 0.891; ΔC-index; + 0.007; P < 0.001). CONCLUSION: Integrating proteomics, metabolomics, and a diabetes-PRS into a clinical model substantially improves type 2 diabetes risk prediction beyond single-omics extensions. Several of the selected proteins and metabolites are on cardiovascular disease pathways, highlighting the link between diabetes and cardiovascular risk. However, the C-index difference between the proteomics extended and full multi-omics extended models is small, and the clinical models extended with proteomics data would be easier to translate into routine care because it needs only the measurement of 15 proteins. External validation and cost-effectiveness analyses are needed to support clinical adoption.

Humans↗

PubMed2026

Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.

BACKGROUND AND AIMS: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. METHODS: All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. RESULTS: Most variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. CONCLUSIONS: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Humans↗

PubMed2026

A Quantitative Lung Mucin Score to Identify Chronic Bronchitis.

BACKGROUND: We previously demonstrated that sputum total mucin concentration is an objective marker for chronic bronchitis (CB). This current study introduces a novel Mucin Quantitative Score (MUCQ) that combines total mucin concentration and mucin composition to improve the assessment of risk, onset of clinically diagnosed disease, and progression of muco-obstructive lung diseases. METHODS: Patients from the SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) cohort were classified as having CB, or not, based on clinical questionnaires. Using the measured total mucin, MUC5AC, and MUC5B concentrations in sputum samples, we calculated MUCQ as [Total mucin]×([MUC5AC]÷[MUC5B])÷100 μg/ml, which is a unitless, weighted concentration score. Our primary outcome was the net reclassification of patients with a diagnosis of CB, or not, based on total mucin concentrations in their sputum compared with using the MUCQ score. Participants were first classified as CB- positive or -negative using a total mucin concentration threshold of 2306 μg/ml, then reclassified using the MUCQ threshold of 4.30. Associated z statistics and a P value for the primary outcome are reported. RESULTS: Among 164 patients in the SPIROMICS cohort with clinically defined CB, using the MUCQ score up-classified 18 patients who were currently smoking to a diagnosis of CB and down-classified 5 patients who were currently smoking and 3 control participants who had never smoked, compared with the classification of CB was based on total mucin concentrations alone (P=0.001). In addition, MUCQ correlated with other clinical and pathological indices of chronic airway disease and airway obstruction. CONCLUSIONS: The MUCQ metric was superior in distinguishing patients with CB compared to a total mucin concentration. Trials are needed to ascertain the prospective use of MUCQ metrics in research and clinical settings for assessment, management, and tracking therapeutic responses in CB and potentially other muco-obstructive conditions. (Funded by the National Institutes of Health and others.).

Humans↗

PubMed2026

Lactate Dehydrogenase and Outcomes in Patients With HF and Reduced Ejection Fraction: Insights From GALACTIC-HF.

BACKGROUND: Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells. Increased LDH levels are a nonspecific measure of cellular injury and may be prognostically important in heart failure (HF). OBJECTIVES: This study aims to assess the relationship between LDH and clinical characteristics and outcomes in heart failure and reduced ejection fraction (HFrEF). METHODS: Using data from GALACTIC-HF, a phase 3, randomized, placebo-controlled trial evaluating the efficacy and safety of omecamtiv mecarbil (OM) in patients with HFrEF, the relationship between LDH and clinical outcomes was analyzed. The incremental value of LDH added to a validated prognostic model (PREDICT-HF) was also calculated using Harrell's C statistic, integrated discrimination index (IDI), and net reclassification index (NRI). RESULTS: In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and high-sensitivity troponin I. Compared with patients in the lowest LDH (Q1: 155 U/L [25th-75th percentile: 144-163 U/L]), the HRs for the primary outcome (first HF event or cardiovascular death) were Q2: 183 U/L (25th-75th percentile: 177-188 U/L); HR: 1.15 [95% CI: 1.02-1.31]; Q3: 207 U/L (25th-75th percentile: 201-215 U/L); HR: 1.39 [95% CI: 1.23-1.58]; and Q4: 253 U/L (25th-75th percentile: 236-280 U/L); HR: 1.84 [95% CI: 1.62-2.08], respectively. Even after adjustment, elevated LDH remained independently associated with higher HR. When added to the PREDICT-HF risk model, baseline LDH improved Harrell's C statistic, IDI, and NRI for the primary outcome. CONCLUSIONS: In GALACTIC-HF, higher LDH levels were independently associated with a higher risk of clinical outcomes in HFrEF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329; EudraCT number: 2016-002299-28).

Humans↗

PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗

PubMed1978

Lobular neoplasia (so-called lobular carcinoma in situ) of the breast.

In a review and reclassification of 5,560 benign epithelial lesions of the breast entered in the files of the Laboratory of Surgical Pathology at Columbia, we found 211 examples of the type of lobular proliferation occurring alone without co-existing infiltrating carcinoma, which we prefer to call lobular neoplasia, but which is generally referred to as noninfiltrating lobular carcinoma in situ. We regard this lesion as a separate distinctive pathological-clinical entity. These 211 cases are studied from a number of parameters, including the ages of the patients, the breast affected, the length of the follow-up, the interval between the initial diagnosis and the frank carcinoma which eventually developed in 17.1 percent of the patients. The relationship of microscopic qualitative and quantitative variations in the lobular neoplasia to subsequent carcinoma was studied; the variations were not found to have any value in predicting subsequent carcinoma. This study is unique in that we have data as to the frequency of a family history of carcinoma in a mother or sister, and also as to the occurrence of gross cystic disease in our patients with lobular neoplasia. We have determined the ratio between the observed and expected numbers of patients developing carcinoma in the several possible combinations of these three factors which predispose to carcinoma. We report that the predisposition is cumulative: in patients in whom all three predisposing factors were present the ratio of observed to expected risk of carcinoma was 13:8. We do not recommend mastectomy for lobular neoplasia, but only systematic follow-up by palpation of the patients' breasts every four months.

Adult↗