A systematic review on machine learning approaches in the diagnosis and prognosis of rare genetic diseases

JALE has received funds from Instituto de Salud Carlos III (Grant# PI20-1126), CIBERER (Grant# PIT21_GCV21), Andalusian University, Research and Innovation Department (PY20-00303, EPIMEN), Andalusian Health Department (Grant# PI027-2020), Asociación Síndrome de Meniere España (ASMES) and Meniere’s Society, UK. PRNV is supported by PY20-00303 Grant (EPIMEN). AMPP is a PhD student in the Biomedicine Program at Universidad de Granada and his salary was supported by Andalusian University, Research and Innovation Department (Grant# PREDOC2021/00343).Background: The diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases. Methods: We performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis. Findings: Our search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations. Conclusions: ML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases.Salud Carlos III PI20-1126CIBERER PIT21_GCV21Research and Innovation Department PY20-00303, EPIMENAndalusian Health Department PI027-2020Asociación Síndrome de Meniere España, ASMESMeniere’s Society, UKAndalusian University, Research and Innovation Department PREDOC2021/0034

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction

The following are available online at https://www.mdpi.com/article/ 10.3390/genes14040831/s1A.A.M.S. received a scholarship from the Philippine Council for Health and Research Development of the Department of Science and Technology (PCHRD-DOST) under the Research Enrichment (Sandwich) Grant of the Accelerated Science and Technology Human Resource Devel- opment Program. O.A.K. was supported by the US National Institutes of Health (NIH)—National Institute on Deafness and Other Communication Disorders (NIDCD) grant T32 DC012280 (to Sue C. Kinnamon and Herman A. Jenkins). This work was supported by the NIH through the NIDCD grants R01 DC019642 (to R.L.P.S.-C. and Ivana V. Yang) and R01 DC013912 (to S.P.G.); and the National Insti- tute of Arthritis and Musculoskeletal and Skin Diseases grant R01 AR068292 (to N.H.-M.). Funding was also provided by Junta de Andalucia, grant Retos en Investigacion PY20_00303 (to J.A.L.-E.).Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.Philippine Council for Health and Research Development of the Department of Science and Technology (PCHRD-DOST) under the Research Enrichment (Sandwich) Grant of the Accelerated Science and Technology Human Resource Development ProgramUS National Institutes of Health (NIH)-National Institute on Deafness and Other Communication Disorders (NIDCD) T32 DC012280NIH through the NIDCD R01 DC019642, R01 DC013912United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) R01 AR068292Junta de Andalucia PY20_0030

4to. Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad. Memoria académica

Este volumen acoge la memoria académica de la Cuarta edición del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad, CITIS 2017, desarrollado entre el 29 de noviembre y el 1 de diciembre de 2017 y organizado por la Universidad Politécnica Salesiana (UPS) en su sede de Guayaquil. El Congreso ofreció un espacio para la presentación, difusión e intercambio de importantes investigaciones nacionales e internacionales ante la comunidad universitaria que se dio cita en el encuentro. El uso de herramientas tecnológicas para la gestión de los trabajos de investigación como la plataforma Open Conference Systems y la web de presentación del Congreso http://citis.blog.ups.edu.ec/, hicieron de CITIS 2017 un verdadero referente entre los congresos que se desarrollaron en el país. La preocupación de nuestra Universidad, de presentar espacios que ayuden a generar nuevos y mejores cambios en la dimensión humana y social de nuestro entorno, hace que se persiga en cada edición del evento la presentación de trabajos con calidad creciente en cuanto a su producción científica. Quienes estuvimos al frente de la organización, dejamos plasmado en estas memorias académicas el intenso y prolífico trabajo de los días de realización del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad al alcance de todos y todas

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Aggregated variant analysis in exomes from familial and early onset Meniere disease patients

Introducción: La enfermedad de Meniere (EM) es una enfermedad rara del oído interno caracterizada por hipoacusia neurosensorial, vértigo episódico, y tinnitus. Aunque la mayoría de los casos de esta enfermedad son esporádicos, en el 6 al 9% de estos pacientes presentan agregación familiar, lo que sugiere una contribución genética en la EM. La EM es una enfermedad compleja, con una gran variabilidad en el fenotipo que se ve acompañada de heterogeneidad genética. Hasta la fecha, solo se han descrito variantes en familias individuales, no encontrándose replicación entre familias no relacionadas. Objetivos: Identificar los principales genes implicados en la EM familiar mediante secuenciación de exoma completo, así como demostrar un efecto agregado de variantes en determinados genes. Así mismo, se identificarán las principales rutas metabólicas implicadas y los resultados serán comparados con una serie de pacientes con EM esporádica. Métodos: Un total de 138 casos con EM (94 pacientes con EM familiar y 44 con EM esporádica) diagnosticados de acuerdo con los criterios definido por la Barany Society fueron seleccionados y secuenciados con el objetivo de buscar variantes raras. Las frecuencias alélicas de las variantes identificadas fueron anotadas para llevar a cabo análisis uni y multivariante. Las frecuencias alélicas en nuestro grupo de pacientes fueron comparadas con las frecuencias encontradas en bases de datos de referencia europeas y españolas. Se llevaron a cabo análisis de sobrerrepresentación para obtener las principales rutas y procesos biológicos afectados. Resultados: En un primer abordaje del trasfondo genético de la EM, se pudo observar que el 40% de los casos familiares y el 68% de los casos esporádicos portaban una variante nueva o ultrarara en un gen ya relacionado con hipoacusia neurosensorial. Analizando estos genes, identificamos un enriquecimiento de variantes en algunos de ellos, destacando sobre los demás el gen que codifica la proteína otogelina, OTOG. Se encontraron un total de 10 variantes en 15 familias no relacionadas. Estudiando la clínica de estos pacientes, se observó que podrían conformar un endofenotipo, caracterizado por hipoacusia pantonal con poca progresión. Finalmente, se llevó a cabo un análisis más general, incluyendo todos los genes codificantes. Los resultados de este análisis sugieren que existe una contribución poligénica y/o polialélica en la EM, siendo diferentes los genes involucrados en la forma familiar y esporádica. Basados en los resultados de estos análisis, se pudo determinar mediante un análisis de sobrerrepresentación que rutas como la guía de señalización axonal podría ser importantes en el desarrollo de la enfermedad. Conclusiones: En esta tesis doctoral se han definido los posibles principales genes y rutas candidatas para la EM familiar, encontrando a su vez una estructura genética diferente a la EM esporádica. Estos resultados podrían ser la base para futuros estudios genéticos y funcionales en la EM.Introduction: Meniere’s disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo and tinnitus. Although most of MD patients are sporadic, familial aggregation is observed in 6-9% of these patients, suggesting a genetic contribution in MD. MD is a complex disease, showing phenotypic heterogeneity as well as genetic heterogeneity. To date, only variants in single families have been associated to familial MD, finding no replication in non-related families. Objectives: To identify the main genes involved in familial MD by whole exome sequencing, and to demonstrate an aggregate effect of variants in certain genes. Furthermore, the main biological processes and pathways will be analyzed, and the results will be compared with sporadic MD patients. Methods: A total of 138 MD patients (94 familial MD patients and 44 sporadic MD patients) diagnosed according to the criteria defined by the Barany Society were recruited and sequenced to look for rare variants. Minor allelic frequencies of identified variants were annotated to undertake a single rare variant and a gene burden analyses. Allelic frequencies were compared with the frequencies from European and Spanish reference datasets. Over-representation analyses were done to identify the main biological processes and pathways. Results: In a first approach of the genetic MD background, we identified that 40% of familial MD patients and 68% of sporadic MD patients carried, at least, a novel or ultrarare variant in a gene linked to sensorineural hearing loss. Analyzing these genes, enrichment of rare variants were identified in some of them, standing out the gene which encodes otogelin, OTOG. Ten variants were found in 15 nonrelated families. Studying the clinical information of these patients, an endophenotype characterized by flat hearing loss with no progression was observed. Finally, we analyzed all the genes within the human genome. The results obtained from this analysis suggest a polygenic and/or a polyallelic contributions in MD, being different the genes involved in familial and sporadic MD. Based on these results, pathways such as axon guidance were identified throughout an over-representation analysis as key pathways in MD. Conclusions: In this doctorate thesis, the main potential genes and pathways for familial MD have been defined, finding a differential genetic background between sporadic and familial MD. These results could be the basis for future genetic and functional studies on MD.Tesis Univ. Granada.Funded by the Luxembourg National Research Fund INTER/Mobility/17/11772209 GrantSupported by ASMES (Asociación Sindrome de Meniere España