Stigma associated with genetic testing for rare diseases-causes and recommendations.

Rare disease (RD) is a term used to describe numerous, heterogeneous diseases that are geographically disparate. Approximately 400 million people worldwide live with an RD equating to roughly 1 in 10 people, with 71.9% of RDs having a genetic origin. RDs present a distinctive set of challenges to people living with rare diseases (PLWRDs), their families, healthcare professionals (HCPs), healthcare system, and societies at large. The possibility of inheriting a genetic disease has a substantial social and psychological impact on affected families. In addition to other concerns, PLWRDs and their families may feel stigmatized, experience guilt, feel blamed, and stress about passing the disease to future generations. Stigma can affect all stages of the journey of PLWRDs and their families, from pre-diagnosis to treatment access, care and support, and compliance. It adversely impacts the quality of life of RD patients. To better explore the impact of stigma associated with genetic testing for RDs, we conducted a literature search on PubMed and Embase databases to identify articles published on stigma and RDs from January 2013 to February 2023. There is a dearth of literature investigating the dynamics of stigma and RD genetic testing. The authors observed that the research into the implications of stigma for patient outcomes in low- and middle-income countries (LMICs) and potential interventions is limited. Herein, the authors present a review of published literature on stigma with a focus on RD genetic testing, the associated challenges, and possible ways to address these.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.

We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

An evaluation of GPT models for phenotype concept recognition.

OBJECTIVE: Clinical deep phenotyping and phenotype annotation play a critical role in both the diagnosis of patients with rare disorders as well as in building computationally-tractable knowledge in the rare disorders field. These processes rely on using ontology concepts, often from the Human Phenotype Ontology, in conjunction with a phenotype concept recognition task (supported usually by machine learning methods) to curate patient profiles or existing scientific literature. With the significant shift in the use of large language models (LLMs) for most NLP tasks, we examine the performance of the latest Generative Pre-trained Transformer (GPT) models underpinning ChatGPT as a foundation for the tasks of clinical phenotyping and phenotype annotation. MATERIALS AND METHODS: The experimental setup of the study included seven prompts of various levels of specificity, two GPT models (gpt-3.5-turbo and gpt-4.0) and two established gold standard corpora for phenotype recognition, one consisting of publication abstracts and the other clinical observations. RESULTS: The best run, using in-context learning, achieved 0.58 document-level F1 score on publication abstracts and 0.75 document-level F1 score on clinical observations, as well as a mention-level F1 score of 0.7, which surpasses the current best in class tool. Without in-context learning, however, performance is significantly below the existing approaches. CONCLUSION: Our experiments show that gpt-4.0 surpasses the state of the art performance if the task is constrained to a subset of the target ontology where there is prior knowledge of the terms that are expected to be matched. While the results are promising, the non-deterministic nature of the outcomes, the high cost and the lack of concordance between different runs using the same prompt and input make the use of these LLMs challenging for this particular task.

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

CRISPR-Cas9-generated PTCHD1 2489T>G stem cells recapitulate patient phenotype when undergoing neural induction.

An estimated 3.5%-5.9% of the global population live with rare diseases, and approximately 80% of these diseases have a genetic cause. Rare genetic diseases are difficult to diagnose, with some affected individuals experiencing diagnostic delays of 5-30 years. Next-generation sequencing has improved clinical diagnostic rates to 33%-48%. In a majority of cases, novel variants potentially causing the disease are discovered. These variants require functional validation in specialist laboratories, resulting in a diagnostic delay. In the interim, the finding is classified as a genetic variant of uncertain significance (VUS) and the affected individual remains undiagnosed. A VUS (PTCHD1 c. 2489T>G) was identified in a child with autistic behavior, global developmental delay, and hypotonia. Loss of function mutations in PTCHD1 are associated with autism spectrum disorder and intellectual disability; however, the molecular function of PTCHD1 and its role in neurodevelopmental disease is unknown. Here, we apply CRISPR gene editing and induced pluripotent stem cell (iPSC) neural disease modeling to assess the variant. During differentiation from iPSCs to neural progenitors, we detect subtle but significant gene signatures in synaptic transmission and muscle contraction pathways. Our work supports the causal link between the genetic variant and the child's phenotype, providing evidence for the variant to be considered a pathogenic variant according to the American College of Medical Genetics and Genomics guidelines. In addition, our study provides molecular data on the role of PTCHD1 in the context of other neurodevelopmental disorders.

Gene editing and cardiac disease modelling for the interpretation of genetic variants of uncertain significance in congenital heart disease.

BACKGROUND: Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis of each VUS is required in specialised laboratories, to determine whether the VUS is disease causative or not, leading to lengthy diagnostic delays. We investigated stem cell cardiac disease modelling and transcriptomics for the purpose of genetic variant classification using a GATA4 (p.Arg283Cys) VUS in a patient with CHD. METHODS: We performed high efficiency CRISPR gene editing with homology directed repair in induced pluripotent stem cells (iPSCs), followed by rapid clonal selection with amplicon sequencing. Genetic variant and healthy matched control cells were compared using cardiomyocyte disease modelling and transcriptomics. RESULTS: Genetic variant and healthy cardiomyocytes similarly expressed Troponin T (cTNNT), and GATA4. Transcriptomics analysis of cardiomyocyte differentiation identified changes consistent with the patient's clinical human phenotype ontology terms. Further, transcriptomics revealed changes in calcium signalling, and cardiomyocyte adrenergic signalling in the variant cells. Functional testing demonstrated, altered action potentials in GATA4 genetic variant cardiomyocytes were consistent with patient cardiac abnormalities. CONCLUSIONS: This work provides in vivo functional studies supportive of a damaging effect on the gene or gene product. Furthermore, we demonstrate the utility of iPSCs, CRISPR gene editing and cardiac disease modelling for genetic variant interpretation. The method can readily be applied to other genetic variants in GATA4 or other genes in cardiac disease, providing a centralised assessment pathway for patient genetic variant interpretation.

The landscape of genomic structural variation in Indigenous Australians.

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.

Indigenous Australian genomes show deep structure and rich novel variation.

The Indigenous peoples of Australia have a rich linguistic and cultural history. How this relates to genetic diversity remains largely unknown because of their limited engagement with genomic studies. Here we analyse the genomes of 159 individuals from four remote Indigenous communities, including people who speak a language (Tiwi) not from the most widespread family (Pama-Nyungan). This large collection of Indigenous Australian genomes was made possible by careful community engagement and consultation. We observe exceptionally strong population structure across Australia, driven by divergence times between communities of 26,000-35,000 years ago and long-term low but stable effective population sizes. This demographic history, including early divergence from Papua New Guinean (47,000 years ago) and Eurasian groups1, has generated the highest proportion of previously undescribed genetic variation seen outside Africa and the most extended homozygosity compared with global samples. A substantial proportion of this variation is not observed in global reference panels or clinical datasets, and variation with predicted functional consequence is more likely to be homozygous than in other populations, with consequent implications for medical genomics2. Our results show that Indigenous Australians are not a single homogeneous genetic group and their genetic relationship with the peoples of New Guinea is not uniform. These patterns imply that the full breadth of Indigenous Australian genetic diversity remains uncharacterized, potentially limiting genomic medicine and equitable healthcare for Indigenous Australians.

Surfacing undiagnosed disease: consideration, counting and coding.

The diagnostic odyssey for people living with rare diseases (PLWRD) is often prolonged for myriad reasons including an initial failure to consider rare disease and challenges to systemically and systematically identifying and tracking undiagnosed diseases across the diagnostic journey. This often results in isolation, uncertainty, a delay to targeted treatments and increase in risk of complications with significant consequences for patient and family wellbeing. This article aims to highlight key time points to consider a rare disease diagnosis along with elements to consider in the potential operational classification for undiagnosed rare diseases during the diagnostic odyssey. We discuss the need to create a coding framework that traverses all stages of the diagnostic odyssey for PLWRD along with the potential benefits this will have to PLWRD and the wider community.

Unmet needs in countries participating in the undiagnosed diseases network international: an international survey considering national health care and economic indicators.

Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated. Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study. Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research. Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.

The psychosocial impact of childhood dementia on children and their parents: a systematic review.

BACKGROUND: Childhood dementias are a group of rare and ultra-rare paediatric conditions clinically characterised by enduring global decline in central nervous system function, associated with a progressive loss of developmentally acquired skills, quality of life and shortened life expectancy. Traditional research, service development and advocacy efforts have been fragmented due to a focus on individual disorders, or groups classified by specific mechanisms or molecular pathogenesis. There are significant knowledge and clinician skill gaps regarding the shared psychosocial impacts of childhood dementia conditions. This systematic review integrates the existing international evidence of the collective psychosocial experiences of parents of children living with dementia. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched four databases to identify original, peer-reviewed research reporting on the psychosocial impacts of childhood dementia, from the parent perspective. We synthesised the data into three thematic categories: parents' healthcare experiences, psychosocial impacts, and information and support needs. RESULTS: Nineteen articles met review criteria, representing 1856 parents. Parents highlighted extensive difficulties connecting with an engaged clinical team and navigating their child's rare, life-limiting, and progressive condition. Psychosocial challenges were manifold and encompassed physical, economic, social, emotional and psychological implications. Access to coordinated healthcare and community-based psychosocial supports was associated with improved parent coping, psychological resilience and reduced psychological isolation. Analysis identified a critical need to prioritize access to integrated family-centred psychosocial supports throughout distinct stages of their child's condition trajectory. CONCLUSION: This review will encourage and guide the development of evidence-based and integrated psychosocial resources to optimise quality of life outcomes for of children with dementia and their families.

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Trends in prenatal diagnosis of congenital anomalies in Western Australia between 1980 and 2020: A population-based study.

BACKGROUND: Advances in screening and diagnostics have changed the way in which we identify and diagnose congenital anomalies. OBJECTIVE: To examine changes in rates of prenatal diagnosis of congenital anomalies over time and by demographic characteristics. METHODS: We undertook a population-based retrospective cohort study of all children born in Western Australia between 1980 and 2020 and diagnosed with a congenital anomaly. Age at diagnosis (prenatal, neonatal, infancy, early childhood or childhood) prevalence (all-type and type-specific), and prevalence ratios (PR) were calculated. We fit joinpoint regression models to describe the average annual percentage change (APC) in prenatal diagnosis over time, and log-binomial regression models to estimate the association between prenatal diagnosis and demographic characteristics. RESULTS: Prenatal diagnosis prevalence between the first (1980-1989: 28.3 per 10,000 births) and last (2005-2014: 156.1 per 10,000 births) decades of the study increased 5.5-fold (95% confidence interval [CI] 5.0, 5.9). Substantial increases were observed for cardiovascular (PR 10.7, 95% CI 8.0, 14.6), urogenital (PR 10.5, 95% CI: 8.7, 12.6) and chromosomal anomalies (PR 7.0, 95% CI 5.9, 8.3). Prenatal diagnosis was positively associated with the birth year (adjusted risk ratio [RR] 1.04, 95% CI 1.03, 1.04), advanced maternal age (RR 1.14, 95% CI 1.11, 1.18), multiple anomalies (RR 2.86, 95% CI 2.77, 2.96) and major anomalies (RR 3.75, 95% CI 3.36, 4.19), and inversely associated with remoteness (RR 0.89, 95% CI: 0.83, 0.95) and Aboriginality (RR 0.90, 95% CI 0.83, 0.97). CONCLUSIONS: Increases in prenatal diagnosis of congenital anomalies were observed in Western Australia from 1980 to 2020, reflecting advances in screening. Prenatal diagnosis was less common in remote regions and in Aboriginal children, strengthening calls for increased provision of antenatal care services for these populations.

Prevalence and trends for Aboriginal and Torres Strait Islander children living with cerebral palsy: A birds-eye view.

AIM: To provide a birds-eye view of the trends of cerebral palsy (CP) for Australian Aboriginal and Torres Strait Islander children and young adults. METHOD: Data were obtained for this population-based observational study from the Australian Cerebral Palsy Register (ACPR), birth years 1995 to 2014. The Indigenous status of children was classified by maternal Aboriginal and Torres Strait Islander or non-Indigenous status. Descriptive statistics were calculated for socio-demographic and clinical characteristics. Prenatal/perinatal and post-neonatal birth prevalence was calculated per 1000 live births and per 10 000 live births respectively, and Poisson regression used to assess trends. RESULTS: Data from the ACPR were available for 514 Aboriginal and Torres Strait Islander individuals with CP. Most children could walk independently (56%) and lived in urban or regional areas (72%). One in five children lived in socioeconomically disadvantaged remote/very remote areas. The birth prevalence of prenatal/perinatal CP declined after the mid-2000s from a high of 4.8 (95% confidence interval 3.2-7.0) to 1.9 per 1000 live births (95% confidence interval 1.1-3.2) (2013-2014), with marked declines observed for term births and teenage mothers. INTERPRETATION: The birth prevalence of CP in Aboriginal and Torres Strait Islander children in Australia declined between the mid-2000s and 2013 to 2014. This birds-eye view provides key stakeholders with new knowledge to advocate for sustainable funding for accessible, culturally safe, antenatal and CP services. WHAT THIS PAPER ADDS: Birth prevalence of cerebral palsy (CP) is beginning to decline for Aboriginal and Torres Strait Islanders. Recent CP birth prevalence for Aboriginal and Torres Strait Islanders is 1.9 per 1000 live births. Most children with CP live in more populated areas rather than remote or very remote areas. One in five Aboriginal and Torres Strait Islander children with CP live in socioeconomically disadvantaged remote areas.

Hospitalizations from Birth to 28 Years in a Population Cohort of Individuals Born with Five Rare Craniofacial Anomalies in Western Australia.

OBJECTIVE: To describe trends, age-specific patterns, and factors influencing hospitalizations for 5 rare craniofacial anomalies (CFAs). METHODS: Data on livebirths (1983-2010; n = 721 019) including rare CFA (craniofacial microsomia, mandibulofacial dysostosis, Pierre Robin sequence, Van der Woude syndrome, and frontonasal dysplasia), episodes of death, and demographic and perinatal factors were identified from the Western Australian Register of Developmental Anomalies, Death Registrations and Midwives Notification System. Information on incident craniofacial and noncraniofacial related admissions, length of hospital stay, and intensive care and emergency-related admissions were identified using principal diagnosis and procedural codes were extracted from the Hospital Morbidity Data Collection and linked to other data sources. Associations of hospitalizations by age groups as well as demographic and perinatal factors were expressed as incidence rate ratio (IRR). RESULTS: The incident hospitalizations were 3 times as high for rare CFA (IRR 3.22-3.72) throughout childhood into adolescence than those without. Children with rare CFA had 3-4 times as many potentially preventable hospitalizations until 18 years of age than those without. Specifically, respiratory infections (IRR 2.13-2.35), ear infections (IRR 7.92-26.28), and oral health-related conditions contributed for most noncraniofacial admissions until the adolescence period. A greater incidence of noncraniofacial related hospitalizations was observed among Indigenous children, births with intrauterine growth restrictions, and families with high socioeconomic disadvantage. CONCLUSIONS: Throughout childhood, individuals with rare CFA had greater hospital service use, specifically for potentially preventable conditions, than those without. These population-level findings can inform new preventive strategies and early disease management targeted toward reducing preventable hospitalizations.

Undiagnosed diseases: Needs and opportunities in 20 countries participating in the Undiagnosed Diseases Network International.

Introduction: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden. Methods: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved. Results: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries. Discussion: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.

3D facial analysis for rare disease diagnosis and treatment monitoring: Proof-Of-Concept plan for hereditary angioedema.

Rare diseases pose a diagnostic conundrum to even the most experienced clinicians around the world. The technology could play an assistive role in hastening the diagnosis process. Data-driven methodologies can identify distinctive disease features and create a definitive diagnostic spectrum. The healthcare professionals in developed and developing nations would benefit immensely from these approaches resulting in quicker diagnosis and enabling early care for the patients. Hereditary Angioedema is one such rare disease that requires a lengthy diagnostic cascade ensuing massive patient inconvenience and cost burden on the healthcare system. It is hypothesized that facial analysis with advanced imaging and algorithmic association can create an ideal diagnostic peer to the clinician while assimilating signs and symptoms in the hospital. 3D photogrammetry has been applied to diagnose rare diseases in various cohorts. The facial features are captured at a granular level in utmost finer detail. A validated and proven algorithm-powered software provides recommendations in real-time. Thus, paving the way for quick and early diagnosis to well-trained or less trained clinicians in different settings around the globe. The generated evidence indicates the strong applicability of 3 D photogrammetry in association with proprietary Cliniface software to Hereditary Angioedema for aiding in the diagnostic process. The approach, mechanism, and beneficial impact have been sketched out appropriately herein. This blueprint for hereditary angioedema may have far-reaching consequences beyond disease diagnosis to benefit all the stakeholders in the healthcare arena including research and new drug development.

Patterns, trends, and factors influencing hospitalizations for craniosynostosis in Western Australia. A population-based study.

Understanding hospital service use among children with a diagnosis of craniosynostosis (CS) is important to improve services and outcomes. This study aimed to describe population-level trends, patterns, and factors influencing hospitalizations for craniosynostosis in Western Australia. Data on live births (1990-2010; n = 554,624) including craniosynostosis, episodes of death, demographic, and perinatal factors were identified from the midwives, birth defects, hospitalizations, and death datasets. Information on craniosynostosis and non-craniosynostosis-related admissions, cumulative length of hospital stay (cLoS), intensive care unit, and emergency department-related admissions were extracted from the hospitalization dataset and linked to other data sources. These associations were examined using negative binomial regression presented as annual percent change and associations of hospitalizations by age groups, demographic, and perinatal factors were expressed as incidence rate ratio (IRR). We found an increasing trend in incident hospitalizations but a marginal decline in cLoS for craniosynostosis over the observed study period. Perinatal conditions, feeding difficulties, nervous system anomalies, respiratory, and other infections contributed to majority of infant non-CS-related admissions.Respiratory infections accounted for about twice the number of admissions for individuals with CS (IRRs 1.94-2.34) across all observed age groups. Higher incidence of non-CS hospitalizations was observed among females, with associated anomalies, to families with highest socioeconomic disadvantage and living in remote areas of the state.   Conclusion: Marginal reduction in the cLoS for CS-related admissions observed over the 21-year period are potentially indicative of improved peri-operative care. However, higher incidence of respiratory infection-related admissions for syndromic synostosis is concerning and requires investigation.