Predicting post-contrast information from contrast agent free cardiac MRI using machine learning: Challenges and methods.

Objectives: Currently, administering contrast agents is necessary for accurately visualizing and quantifying presence, location, and extent of myocardial infarction (MI) with cardiac magnetic resonance (CMR). In this study, our objective is to investigate and analyze pre- and post-contrast CMR images with the goal of predicting post-contrast information using pre-contrast information only. We propose methods and identify challenges. Methods: The study population consists of 272 retrospectively selected CMR studies with diagnoses of MI (n = 108) and healthy controls (n = 164). We describe a pipeline for pre-processing this dataset for analysis. After data feature engineering, 722 cine short-axis (SAX) images and segmentation mask pairs were used for experimentation. This constitutes 506, 108, and 108 pairs for the training, validation, and testing sets, respectively. We use deep learning (DL) segmentation (UNet) and classification (ResNet50) models to discover the extent and location of the scar and classify between the ischemic cases and healthy cases (i.e., cases with no regional myocardial scar) from the pre-contrast cine SAX image frames, respectively. We then capture complex data patterns that represent subtle signal and functional changes in the cine SAX images due to MI using optical flow, rate of change of myocardial area, and radiomics data. We apply this dataset to explore two supervised learning methods, namely, the support vector machines (SVM) and the decision tree (DT) methods, to develop predictive models for classifying pre-contrast cine SAX images as being a case of MI or healthy. Results: Overall, for the UNet segmentation model, the performance based on the mean Dice score for the test set (n = 108) is 0.75 (±0.20) for the endocardium, 0.51 (±0.21) for the epicardium and 0.20 (±0.17) for the scar. For the classification task, the accuracy, F1 and precision scores of 0.68, 0.69, and 0.64, respectively, were achieved with the SVM model, and of 0.62, 0.63, and 0.72, respectively, with the DT model. Conclusion: We have presented some promising approaches involving DL, SVM, and DT methods in an attempt to accurately predict contrast information from non-contrast images. While our initial results are modest for this challenging task, this area of research still poses several open problems.

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. MAIN BODY: We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. CONCLUSIONS: WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

Variation in left ventricular cardiac magnetic resonance normal reference ranges: systematic review and meta-analysis.

AIMS: To determine population-related and technical sources of variation in cardiac magnetic resonance (CMR) reference ranges for left ventricular (LV) quantification through a formal systematic review and meta-analysis. METHODS AND RESULTS: This study is registered with the International Prospective Register of Systematic Reviews (CRD42019147161). Relevant studies were identified through electronic searches and assessed by two independent reviewers based on predefined criteria. Fifteen studies comprising 2132 women and 1890 men aged 20-91 years are included in the analysis. Pooled LV reference ranges calculated using random effects meta-analysis with inverse variance weighting revealed significant differences by age, sex, and ethnicity. Men had larger LV volumes and higher LV mass than women [LV end-diastolic volume (mean difference = 6.1 mL/m2, P-value = 0.014), LV end-systolic volume (MD = 4 mL/m2, P-value = 0.033), LV mass (mean difference = 12 g/m2, P-value = 7.8 × 10-9)]. Younger individuals had larger LV end-diastolic volumes than older ages (20-40 years vs. ≥65 years: women MD = 14.0 mL/m2, men MD = 14.7 mL/m2). East Asians (Chinese, Korean, Singaporean-Chinese, n = 514) had lower LV mass than Caucasians (women: MD = 6.4 g/m2, P-value = 0.016; men: MD = 9.8 g/m2, P-value = 6.7 × 10-5). Between-study heterogeneity was high for all LV parameters despite stratification by population-related factors. Sensitivity analyses identified differences in contouring methodology, magnet strength, and post-processing software as potential sources of heterogeneity. CONCLUSION: There is significant variation between CMR normal reference ranges due to multiple population-related and technical factors. Whilst there is need for population-stratified reference ranges, limited sample sizes and technical heterogeneity precludes derivation of meaningful unified ranges from existing reports. Wider representation of different populations and standardization of image analysis is urgently needed to establish such reference distributions.

HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence.

CONTEXT: Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. OBJECTIVE: The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. DESIGN, SETTING, PATIENTS: Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. RESULTS: Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. CONCLUSIONS: Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Recent Trends and Potential Drivers of Non-invasive Cardiovascular Imaging Use in the United States of America and England.

Background: Non-invasive Cardiovascular imaging (NICI), including cardiovascular magnetic resonance (CMR) imaging provides important information to guide the management of patients with cardiovascular conditions. Current rates of NICI use and potential policy determinants in the United States of America (US) and England remain unexplored. Methods: We compared NICI activity in the US (Medicare fee-for-service, 2011-2015) and England (National Health Service, 2012-2016). We reviewed recommendations related to CMR from Clinical Practice Guidelines, Appropriate Use Criteria (AUC), and Choosing Wisely. We then categorized recommendations according to whether CMR was the only recommended NICI technique (substitutable indications). Reimbursement policies in both settings were systematically collated and reviewed using publicly available information. Results: The 2015 rate of NICI activity in the US was 3.1 times higher than in England (31,055 vs. 9,916 per 100,000 beneficiaries). The proportion of CMR of all NICI was small in both jurisdictions, but nuclear cardiac imaging was more frequent in the US in absolute and relative terms. American and European CPGs were similar, both in terms of number of recommendations and proportions of indications where CMR was not the only recommended NICI technique (substitutable indications). Reimbursement schemes for NICI activity differed for physicians and hospitals between the two settings. Conclusions: Fee-for-service physician compensation in the US for NICI may contribute to higher NICI activity compared to England where physicians are salaried. Reimbursement arrangements for the performance of the test may contribute to the higher proportion of nuclear cardiac imaging out of the total NICI activity. Differences in CPG recommendations appear not to explain the variation in NICI activity between the US and England.