Machine Learning towards General Medical Image Segmentation

The quality of patient care associated with diagnostic radiology is proportionate to a physician\u27s workload. Segmentation is a fundamental limiting precursor to diagnostic and therapeutic procedures. Advances in machine learning aims to increase diagnostic efficiency to replace single applications with generalized algorithms. We approached segmentation as a multitask shape regression problem, simultaneously predicting coordinates on an object\u27s contour while jointly capturing global shape information. Shape regression models inherent point correlations to recover ambiguous boundaries not supported by clear edges and region homogeneity. Its capabilities was investigated using multi-output support vector regression (MSVR) on head and neck (HaN) CT images. Subsequently, we incorporated multiplane and multimodality spinal images and presented the first deep learning multiapplication framework for shape regression, the holistic multitask regression network (HMR-Net). MSVR and HMR-Net\u27s performance were comparable or superior to state-of-the-art algorithms. Multiapplication frameworks bridges any technical knowledge gaps and increases workflow efficiency

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations

Chinese family with diffuse oesophageal leiomyomatosis: A new COL4A5/COL4A6 deletion and a case of gonosomal mosaicism

© 2015 Liu et al. Background: Diffuse oesophageal leiomyomatosis (DOL) is a rare disorder characterized by tumorous overgrowth of the muscular wall of the oesophagus. DOL is present in 5 % of Alport syndrome (AS) patients. AS is a rare hereditary disease that involves varying degrees of hearing impairment, ocular changes and progressive glomerulonephritis leading to renal failure. In DOL-AS patients, the genetic defect consists of a deletion involving the COL4A5 and COL4A6 genes on the X chromosome. Case presentation: We report a two-generation family (4 individuals; parents and two children, one male and one female) with two members (mother and son) affected with oesophageal leiomyomatosis. Signs of potential renal failure, which characterizes AS, were only apparent in the index patient (son) 2 years and three months after the initial diagnosis of DOL. Blood DNA from the four family members were submitted to exome sequencing and array genotyping to perform a genome wide screening for disease causal single nucleotide (SN) and copy number (CN) variations. Analyses revealed a new 40kb deletion encompassing from intron 2 of COL4A5 to intron 1 of COL4A6 at Xq22.3. The breakpoints were also identified. Possible confounding pathogenic exonic variants in genes known to be involved in other extracellular matrices disorders were also shared by the two affected individuals. Meticulous analysis of the maternal DNA revealed a case of gonosomal mosaicism. Conclusions: This is the first report of gonadosomal mosaicism associated to DOL-AS.published_or_final_versio

Targeted next-generation sequencing on hirschsprung disease: A pilot study exploits DNA pooling

To adopt an efficient approach of identifying rare variants possibly related to Hirschsprung disease (HSCR), a pilot study was set up to evaluate the performance of a newly designed protocol for next generation targeted resquencing. In total, 20 Chinese HSCR patients and 20 Chinese sex-matched individuals with no HSCR were included, for which coding sequences (CDS) of 62 genes known to be in signaling pathways relevant to enteric nervous system development were selected for capture and sequencing. Blood DNAs from eight pools of five cases or controls were enriched by PCR-based RainDance technology (RDT) and then sequenced on a 454 FLX platform. As technical validation, five patients from case Pool-3 were also independently enriched by RDT, indexed with barcode and sequenced with sufficient coverage. Assessment for CDS single nucleotide variants showed DNA pooling performed well (specificity/sensitivity at 98.4%/83.7%) at the common variant level; but relatively worse (specificity/sensitivity at 65.5%/61.3%) at the rare variant level. Further Sanger sequencing only validated five out of 12 rare damaging variants likely involved in HSCR. Hence more improvement at variant detection and sequencing technology is needed to realize the potential of DNA pooling for large-scale resequencing projects. © 2014 John Wiley & Sons Ltd/University College London.postprin

Depletion of the IKBKAP ortholog in zebrafish leads to hirschsprung disease-like phenotype

© The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved. AIM: To investigate the role of IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) in the development of enteric nervous system (ENS) and Hirschsprung disease (HSCR). METHODS: In this study, we injected a morpholino that blocked the translation of ikbkap protein to 1-cell stage zebrafish embryos. The phenotype in the ENS was analysed by antibody staining of the pan-neuronal marker HuC/D followed by enteric neuron counting. The mean numbers of enteric neurons were compared between the morphant and the control. We also studied the expressions of ret and phox2bb, which are involved in ENS development, in the ikbkap morpholino injected embryos by quantitative reverse transcriptase polymerase chain reaction and compared them with the control. RESULTS: We observed aganglionosis (χ2, P < 0.01) and a reduced number of enteric neurons (38.8 ± 9.9 vs 50.2 ± 17.3, P < 0.05) in the zebrafish embryos injected with ikbkap translation-blocking morpholino (morphant) when compared with the control embryos. Specificity of the morpholino was confirmed by similar results obtained using a second non-overlapping morpholino that blocked the translation of ikbkap. We further studied the morphant by analysing the expression levels of genes involved in ENS development such as ret, phox2bb and sox10, and found that phox2bb, the ortholog of human PHOX2B, was significantly down-regulated (0.51 ± 0.15 vs 1.00 ± 0, P < 0.05). Although we also observed a reduction in the expression of ret, the difference was not significant. CONCLUSION: Loss of IKBKAP contributed to HSCR as demonstrated by functional analysis in zebrafish embryos.Link_to_subscribed_fulltex

Tackling dementia globally: the Global Dementia Prevention Program (GloDePP) collaboration

Daniel Reidpath - ORCID: 0000-0002-8796-0420 https://orcid.org/0000-0002-8796-0420http://dx.doi.org/10.7189/jogh.09.0201039pubpub

Haplotype Analysis Reveals a Possible Founder Effect of RET Mutation R114H for Hirschsprung's Disease in the Chinese Population

Background Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RETR114H) has recently been identified in ~6-7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RETR114H in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population. Methodology and Principal Findings To test whether all RETR114H were originated from a single mutational event, we predicted the approximate age of RETR114H by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4-23 generations old depending on growth rate. We reasoned that if RETR114H was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RETR114H patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RETR114H that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients. Conclusions This suggests that RETR114H is a founder mutation for HSCR in the Chinese population. © 2010 Cornes et al.published_or_final_versio

Guidance for health care worker surveys in humanitarian contexts in LMICs

Developed by the Social Sciences Analysis Cell (CASS) and the Research Roadmap to support those working with communities and healthcare workers in humanitarian and emergency contexts This document has been developed for response actors working in humanitarian contexts who seek rapid approaches to gathering evidence about the experience of healthcare workers, and the communities of which they are a part. Understanding healthcare worker experience is critical to inform and guide humanitarian programming and effective strategies to promote IPC, identify psychosocial support needs. This evidence also informs humanitarian programming that interacts with HCWs and facilities such as nutrition, health reinforcement, communication, SGBV and gender. In low- and middle-income countries (LMIC), healthcare workers (HCW) are often faced with limited resources, equipment, performance support and even formal training to provide the life-saving work expected of them. In humanitarian contexts1 , where human resources are also scarce, HCWs may comprise formally trained doctors, nurses, pharmacists, dentists, allied health professionals etc. as well as community members who perform formal health worker related duties with little or no trainingi . These HCWs frequently work in contexts of multiple public health crises, including COVID-19. Their work will be affected by availability of resources (limited supplies, materials), behaviour and emotion (fear), flows of (mis)information (e.g. understanding of expected infection prevention and control (IPC) measures) or services (healthcare policies, services and use). Multiple factors can therefore impact patients, HCWs and their families, not only in terms of risk of exposure to COVID-19, but secondary health, socio-economic and psycho-social risks, as well as constraints that interrupt or hinder healthcare provision such as physical distancing practices. The development and dissemination of training and guidance for HCWs is important for any new infectious disease outbreak. Equally, evaluation of their appropriateness and utility, their impacts on HCW performance and behaviour, and their effectiveness (perceived or measured against programmatic outcome indicators) is important to adapt and improve the appropriateness and effectiveness of resources for HCWs. We recommend HCW surveys are included as a critical component of research associated to humanitarian programming for communities and community health outcomes