Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening. Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The LRS derived from SAFHS as well as its recalibrated version were validated in an independent cohort from Australia – the AusDiab cohort. The participants were T2D-free at baseline and followed for 9197 person-years in the SAFHS cohort (n = 771) and 5930 person-years in the AusDiab cohort (n = 644). Statistically and clinically improved T2D prediction was evaluated with established statistical parameters in both cohorts. Modeling studies were conducted to determine whether the use of LRS would be cost-effective for T2D screening. The main outcome measures included accuracy and incremental value of the LRS over routinely used clinical predictors of T2D risk; validation of these results in an independent cohort and cost-effectiveness of including LRS in screening/intervention programs for T2D. The LRS was based on plasma concentration of dihydroceramide 18:0, lysoalkylphosphatidylcholine 22:1 and triacyglycerol 16:0/18:0/18:1. The score predicted future T2D independently of prediabetes with an accuracy of 76 %. Even in the subset of initially euglycemic individuals, the LRS improved T2D prediction. In the AusDiab cohort, the LRS continued to predict T2D significantly and independently. When combined with risk-stratification methods currently used in clinical practice, the LRS significantly improved the model fit (p < 0.001), information content (p < 0.001), discrimination (p < 0.001) and reclassification (p < 0.001) in both cohorts. Modeling studies demonstrated that LRS-based risk-stratification combined with metformin supplementation for high-risk individuals was the most cost-effective strategy for T2D prevention. Considering the novelty, incremental value and cost-effectiveness of LRS it should be used for risk-stratification of future T2D.

There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively. Data for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h 2 r = 0.52, p = 1.1 × 10−5) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism. Our results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype.

Objectives Early detection is of crucial importance for prevention of type 2 diabetes and pre-diabetes. Diagnosis of these conditions relies on the oral glucose tolerance test and haemoglobin A1c estimation which are invasive and challenging for large-scale screening. We aimed to combine the non-invasive nature of ECG with the power of machine learning to detect diabetes and pre-diabetes. Methods Data for this study come from Diabetes in Sindhi Families in Nagpur study of ethnically endogenous Sindhi population from central India. Final dataset included clinical data from 1262 individuals and 10 461 time-aligned heartbeats recorded digitally. The dataset was split into a training set, a validation set and independent test set (8892, 523 and 1046 beats, respectively). The ECG recordings were processed with median filtering, band-pass filtering and standard scaling. Minority oversampling was undertaken to balance the training dataset before initiation of training. Extreme gradient boosting (XGBoost) was used to train the classifier that used the signal-processed ECG as input and predicted the membership to ‘no diabetes’, pre-diabetes or type 2 diabetes classes (defined according to American Diabetes Association criteria). Results Prevalence of type 2 diabetes and pre-diabetes was ~30% and ~14%, respectively. Training was smooth and quick (convergence achieved within 40 epochs). In the independent test set, the DiaBeats algorithm predicted the classes with 97.1% precision, 96.2% recall, 96.8% accuracy and 96.6% F1 score. The calibrated model had a low calibration error (0.06). The feature importance maps indicated that leads III, augmented Vector Left (aVL), V4, V5 and V6 were most contributory to the classification performance. The predictions matched the clinical expectations based on the biological mechanisms of cardiac involvement in diabetes. Conclusions Machine-learning-based DiaBeats algorithm using ECG signal data accurately predicted diabetes-related classes. This algorithm can help in early detection of diabetes and pre-diabetes after robust validation in external datasets.

Objectives There exists a wide gap in the availability of mechanical ventilator devices and their acute need in the context of the COVID-19 pandemic. An initial triaging method that accurately identifies the need for mechanical ventilation in hospitalised patients with COVID-19 is needed. We aimed to investigate if a potentially deteriorating clinical course in hospitalised patients with COVID-19 can be detected using all X-ray images taken during hospitalisation. Methods We exploited the well-established DenseNet121 deep learning architecture for this purpose on 663 X-ray images acquired from 528 hospitalised patients with COVID-19. Two Pulmonary and Critical Care experts blindly and independently evaluated the same X-ray images for the purpose of validation. Results We found that our deep learning model predicted the need for mechanical ventilation with a high accuracy, sensitivity and specificity (90.06%, 86.34% and 84.38%, respectively). This prediction was done approximately 3 days ahead of the actual intubation event. Our model also outperformed two Pulmonary and Critical Care experts who evaluated the same X-ray images and provided an incremental accuracy of 7.24%–13.25%. Conclusions Our deep learning model accurately predicted the need for mechanical ventilation early during hospitalisation of patients with COVID-19. Until effective preventive or treatment measures become widely available for patients with COVID-19, prognostic stratification as provided by our model is likely to be highly valuable.

Chronic kidney disease (CKD) affects 15% of the adult population in the US and has contributed to a 52% increase in cost burden from 2002 to 2016.^1,2 A key pathophysiological indicator of CKD is interstitial fibrosis and tubular atrophy (IFTA), which is associated with estimated glomerular filtration rate (eGFR),³ future decline in kidney function, and development of kidney failure.⁴ Furthermore, IFTA incrementally improves the value of baseline proteinuria and eGFR to predict clinical outcomes of CKD⁵ irrespective of the underlying causes.^5,6 Currently, the challenge is to have an accurate, noninvasive method to quantify IFTA because histopathological grading of kidney biopsy core by a nephropathologist is the only accepted method to quantify IFTA. In addition to being invasive, kidney biopsy is associated with bleeding complications, provides only a snapshot of IFTA, and is subject to sampling error.^7,8 Consequently and importantly, most patients with CKD who will eventually need kidney replacement therapy⁹ never undergo a kidney biopsy^10,11 and represent a missed clinical opportunity.