The growing needs of genetic counselling-Feasibility in utilization of tele-genetic counselling in Asia and Hong Kong.

The need for the expansion of genomic services has been at a record time high in the past decade. As technological advancement continues to strengthen the entire genetic and genomic pipeline and clinical operational workflow, the major challenge remains to be the speed of workforce development to meet service growth. In particular, the international expansion of genetic counselling (GC) services has been a topic of interest for the past few years. GC is an emerging profession in most of Asia, and in many countries the profession of GC often refers to physicians or front-line health workers with expertise in genetics to provide GC services rather than being a specific independent profession. As genetic and genomic services, especially pre-test and post-test GC, expand globally, the need to tackle the longstanding obstacles of GC personnel shortage and funding issues must not be overlooked. There is an urgent need internationally, and especially in Asia, where GC profession is comparatively less well-established, to seek alternative approaches to meet service demand. The present review examines the global development and feasibility of tele-genetics and tele-genetic counselling (TGC), and serves as the foundation to explore a possible roadmap in Hong Kong via the Hong Kong Genome Project.

Rare disease emerging as a global public health priority.

The genomics revolution over the past three decades has led to great strides in rare disease (RD) research, which presents a major shift in global policy landscape. While RDs are individually rare, there are common challenges and unmet medical and social needs experienced by the RD population globally. The various disabilities arising from RDs as well as diagnostic and treatment uncertainty were demonstrated to have detrimental influence on the health, psychosocial, and economic aspects of RD families. Despite the collective large number of patients and families affected by RDs internationally, the general lack of public awareness and expertise constraints have neglected and marginalized the RD population in health systems and in health- and social-care policies. The current Coronavirus Disease of 2019 (COVID-19) pandemic has exposed the long-standing and fundamental challenges of the RD population, and has reminded us of the critical need of addressing the systemic inequalities and widespread disparities across populations and jurisdictions. Owing to the commonality in goals between RD movements and universal health coverage targets, the United Nations (UN) has highlighted the importance of recognizing RDs in policies, and has recently adopted the UN Resolution to promote greater integration of RDs in the UN agenda, advancing UN's commitment in achieving the 2030 Sustainable Development Goals of "leav[ing] no one behind." Governments have also started to launch Genome Projects in their respective jurisdictions, aiming to integrate genomic medicine into mainstream healthcare. In this paper, we review the challenges experienced by the RD population, the establishment and adoption of RD policies, and the state of evidence in addressing these challenges from a global perspective. The Hong Kong Genome Project was illustrated as a case study to highlight the role of Genome Projects in enhancing clinical application of genomic medicine for personalized medicine and in improving equity of access and return in global genomics. Through reviewing what has been achieved to date, this paper will provide future directions as RD emerges as a global public health priority, in hopes of moving a step toward a more equitable and inclusive community for the RD population in times of pandemics and beyond.

Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese.

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

Perception of personalized medicine, pharmacogenomics, and genetic testing among undergraduates in Hong Kong.

BACKGROUND: The global development and advancement of genomic medicine in the recent decade has accelerated the implementation of personalized medicine (PM) and pharmacogenomics (PGx) into clinical practice, while catalyzing the emergence of genetic testing (GT) with relevant ethical, legal, and social implications (ELSI). RESULTS: The perception of university undergraduates with regards to PM and PGx was investigated, and 80% of undergraduates valued PM as a promising healthcare model with 66% indicating awareness of personal genome testing companies. When asked about the curriculum design towards PM and PGx, compared to undergraduates in non-medically related curriculum, those studying in medically related curriculum had an adjusted 7.2 odds of perceiving that their curriculum was well-designed for learning PGx (95% CI 3.6-14.6) and a 3.7 odds of perceiving that PGx was important in their study (95% CI 2.0-6.8). Despite this, only 16% of medically related curriculum undergraduates would consider embarking on future education on PM. When asked about their perceptions on GT, 60% rated their genetic knowledge as "School Biology" level or below while 76% would consider undergoing a genetic test. As for ELSI, 75% of undergraduates perceived that they were aware of ethical issues of GT in general, particularly on "Patient Privacy" (80%) and "Data Confidentiality" (68%). Undergraduates were also asked about their perceived reaction upon receiving an unfavorable result from GT, and over half of the participants perceived that they would feel "helpless or pessimistic" (56%), "inadequate or different" (59%), and "disadvantaged at job seeking" (59%), while older undergraduates had an adjusted 2.0 odds of holding the latter opinion (95% CI 1.1-3.5), compared to younger undergraduates. CONCLUSION: Hong Kong undergraduates showed a high awareness of PM but insufficient genetic knowledge and low interest in pursuing a career towards PM. They were generally aware of ethical issues of GT and especially concerned about patient privacy and data confidentiality. There was a predominance of pessimistic views towards unfavorable testing results. This study calls for the attention to evaluate education and talent development on genomics, and update existing legal frameworks on genetic testing in Hong Kong.

Hospital mortality in patients with rare diseases during pandemics: lessons learnt from the COVID-19 and SARS pandemics.

BACKGROUND: The threat and experience of pandemics occur differently for different groups. The rare disease population is at particular risk of being further marginalised during pandemics. In this study, our objective was to assess the hospital mortality patterns in the rare disease and the general populations during the coronavirus disease of 2019 (COVID-19) and severe acute respiratory syndrome (SARS) pandemics in Hong Kong. METHODS: All admission records during the COVID-19 pandemic (January 23-August 23, 2020) and SARS pandemic (March 11-June 30, 2003) were extracted from the local public healthcare database. Patients with rare diseases were identified using one or more of the 1084 10th version International Classification of Diseases and Related Health Problems (ICD-10) codes cross-referenced with 467 ORPHAcodes. Hospital mortality patterns were compared in patients with and without COVID-19/SARS infection. Admission records during the same period in 2019 and 2002 were retrieved for comparison. RESULTS: During the COVID-19 pandemic, 407,219 patients were admitted to one or more of the 43 public hospitals in Hong Kong, of which, 13,894 were patients with rare diseases (3.4%). A total of 4381 and 77 patients from the general and rare disease populations were infected with COVID-19. Rare disease patients had an adjusted 3.4 times odds of COVID-19-related hospital mortality compared with that of the general population (95% C.I. 1.24-9.41). COVID-19-related mortality was almost exclusively seen in patients ≥ 60 years. While age-related increase in mortality was also observed for the general population during the SARS pandemic, the pattern observed in the rare disease population was significantly different, with a 12.5 times higher SARS-related mortality observed in rare disease patients ≤ 18 years than those in the general population (12.5% vs 1.0%). Patients admitted during the same pandemic periods without coronavirus infection had a significantly higher hospital mortality compared with those admitted one year before the pandemic (p < 0.001). CONCLUSION: This population-based study demonstrated the differential impacts of the COVID-19 and SARS pandemics on the rare disease population. In the era of budget and resource scarcity, this study warrants cautious healthcare planning, with consideration of the rare disease population in healthcare prioritisation.

Preparing genomic revolution: Attitudes, clinical practice, and training needs in delivering genetic counseling in primary care in Hong Kong and Shenzhen, China.

PURPOSE: The aim was to evaluate knowledge, attitudes, and clinical practice concerning medical genetics, genetic testing, and counseling among primary care physicians (PCPs) in Hong Kong and Shenzhen, China. METHODS: The University of Hong Kong (HKU), HKU-Shenzhen Hospital, and Shenzhen Health Capacity Building and Continuing Education Center invited PCPs from Hong Kong and Shenzhen to participate in an online survey. RESULTS: The survey was completed by 151 PCPs and 258 PCPs from Hong Kong and Shenzhen, respectively. The majority agreed it was important to keep current with genetics (91%) and that personalized medicine was the future of healthcare (86%), yet only 10% reported that they had postgraduate training in genomic medicine. Seventeen percent of Hong Kong and 40% of Shenzhen's PCPs encountered genetic-related cases in the past 6 months, and they identified insufficient knowledge, few training opportunities, and self-rated low confidence in their skillsets as main barriers. CONCLUSIONS: Our survey shows that Hong Kong and Shenzhen's PCPs are not yet fully utilizing potential benefits of genomic medicine in their clinical practice, which could be addressed with a combination of easily accessible educational resources, clear referral pathways and guidelines on genetic diseases, and cross-specialty collaboration between healthcare systems and professional bodies.

Prevalence and healthcare utilization of rare neurological diseases in Hong Kong: 2014-2018.

BACKGROUND: There has been increasing attention focused on the epidemiology of rare diseases (RDs) in recent years. Rare neurological diseases (RNDs) constitute a significant proportion of RDs; however, relevant research is still lacking. METHODS: A list of ICD-10 codes corresponding to RNDs was compiled using adaptations from the Orphanet Classification of Rare Diseases, and classified into rare epilepsy, movement-related, neurocutaneous, neuroimmune, neurometabolic and neurodegenerative, neuromuscular and other RNDs. Using the Clinical Data Analysis and Reporting System, which holds public hospital healthcare records of Hong Kong anonymously, we calculated the prevalence and healthcare utilization of RND patients between 2014 and 2018. The list of RNDs was also used to review relevant pharmacological trials within the International Clinical Trials Registry Platform between 2009 and 2018. RESULTS: The prevalence of RNDs in Hong Kong is 3.6 in 1,000 individuals. Patients with RNDs had frequent emergency department, outpatient and inpatient healthcare utilization. The average annual cost per patient is estimated at HKD 182,075 (€ 19,688). Different categories of RNDs showed different patterns of healthcare utilization. Moreover, there were only 677 RND-related pharmacological trials during the study period, and no trial was found for 78% of RNDs. CONCLUSIONS: This is one of the first population studies on the prevalence and healthcare utilization patterns of RNDs, with comprehensive reviews of RND-related pharmacological research. It shows high healthcare utilization rates among patients with RNDs, as well as a wide research gap in many RNDs. We call for better attention and tailored healthcare for these patients.

A thematic study: impact of COVID-19 pandemic on rare disease organisations and patients across ten jurisdictions in the Asia Pacific region.

BACKGROUND: This study assesses the areas and extent of impact of the Coronavirus Disease of 2019 (COVID-19) pandemic on rare disease (RD) organisations in the Asia Pacific region. There is no existing literature that focuses on such impact on RD organisations in any jurisdictions, nor RD populations across multiple jurisdictions in the Asia Pacific region. A cross-sectional survey was distributed to RD organisations between April and May 2020. Quantitative and qualitative data on the impact of COVID-19 on RD organisations and patients were collected from the organisation representative's perspective. Qualitative data was analysed using thematic analysis. A follow-up focus group meeting was conducted in August 2020 to validate the survey findings and to discuss specific needs, support and recommendations for sustainable healthcare systems during the pandemic. RESULTS: A total of 80 RD organisations from Australia, Hong Kong Special Administrative Region of China, India, Japan, mainland China, Malaysia, New Zealand, the Philippines, Singapore and Taiwan participated in the study. Of all, 89% were concerned about the impact of pandemic on their organisations. Results indicate that 63% of the organisations functioned at a reduced capacity and 42% stated a decrease in funding as their biggest challenge. Overall, 95% believed their patients were impacted, particularly in healthcare access, social lives, physical health, psychological health and financial impact. Specifically, 43% identified the reduced healthcare access as their top impact, followed by 26% about the impact on daily living and social life. Focus group meeting discussed differential impact across jurisdictions and point towards telemedicine and digitalisation as potential solutions. CONCLUSIONS: This serves as the first study to assess the impact of COVID-19 on RD patients and organisations across multiple jurisdictions in the Asia Pacific region, identifying major themes on the impact on both RD patients and organisations. By including 80 organisations from ten jurisdictions, our study presents the most comprehensive assessment of the pandemic's impact to date. It highlights the need for mental health support and sheds light on moving towards telemedicine and digitalisation of organisation operation, which constitutes a sustainable model in times of pandemics and beyond.

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population.

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

Cost-effectiveness analysis of chromosomal microarray as a primary test for prenatal diagnosis in Hong Kong.

BACKGROUND: Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong. METHODS: Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women's willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis. RESULTS: The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper (p ≤ 0.05). Taking into account women's willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made. CONCLUSION: By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong.

Evaluating the Clinical Utility of Genome Sequencing for Cytogenetically Balanced Chromosomal Abnormalities in Prenatal Diagnosis.

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.

Healthcare burden of rare diseases in Hong Kong - adopting ORPHAcodes in ICD-10 based healthcare administrative datasets.

BACKGROUND: The burden of rare diseases is important for healthcare planning but difficult to estimate. This has been facilitated by the development of ORPHAcodes, a comprehensive classification and coding system for rare diseases developed by the international consortium Orphanet, with cross-references to the 10th version of the International Classification of Diseases and Related Health Problems (ICD-10). A recent study in Western Australia made use of this cross-referencing to identify rare diseases-related admissions in health administrative datasets. Such methodology was adopted in Hong Kong, which has a population of 7 million comprising of 92% ethnic Chinese, with over 80% of admissions taking place in the public hospitals and available for review from the local public healthcare database. MAIN BODY: Our objective was to identify the inpatient healthcare burden of rare diseases in Hong Kong. We extracted admission records of all patients coded with one or more of the 1084 ICD-10 codes cross referenced with 467 ORPHAcodes during the study period from 1st January 2005 to 31st December 2016. We further analysed rare disease-related inpatient healthcare cost using a subset of patients admitted during 1st April 2015 - 31st March 2016. A total number of 546,673 admissions were identified, representing 3.2% of total admissions during the study period. By the end of the study, 109,535 patients were alive, representing 1.5% of the overall population. Prevalence of rare diseases was found to be 1 in 67 in the Hong Kong population. The most common rare disease category in the paediatric age group was 'rare developmental defect during embryogenesis'; whereas that amongst adults was 'rare haematologic disease'. The aforementioned subset of patients accounted for 330,091 inpatient-days, placing the estimated total inpatient cost for rare disease population at HKD$1,594,339,530 i.e. 4.3% of total inpatient cost in 2015-2016. CONCLUSION: Cross referencing between ICD-10 and ORPHAcodes may be adopted in different healthcare datasets for international comparison. Despite differences in the prevalence of individual disease, the disparity between rare disease prevalence (1.5%) and associated inpatient cost (4.3%) in Hong Kong reflects the importance of rare diseases in healthcare policies.