Computer-assisted patient identification tool in inborn errors of metabolism - potential for rare disease patient registry and big data analysis.

BACKGROUND: Patient registries are crucial for rare disease management. However, manual registry construction is labor-intensive and often not user-friendly. Our goal is to establish Hong Kong's first computer-assisted patient identification tool for rare diseases, starting with inborn errors of metabolism (IEM). METHODS: Patient data from 2010 to 2019 was retrieved from electronic databases. Through big data analytics, patient data were filtered based on specific IEM-related biochemical and genetic tests. Clinical notes were analyzed using a rule-based natural language processing technique called regular expression. The algorithm classified each extracted paragraph as "IEM-related" or "not IEM-related." Pathologists reviewed the paragraphs for curation, and the algorithm's performance was evaluated. RESULTS: Out of 46,419 patients with IEM-related tests, the algorithm identified 100 as "IEM-related." After pathologists' validation, 96 cases were confirmed as true IEM, with 1 uncertain case and 3 false positives. A secondary ascertainment yielded a sensitivity of 92.3% compared to our previously published IEM cohort. CONCLUSIONS: Our artificial intelligence approach provides a novel method to identify IEM patients, facilitating the creation of a centralized, computer-assisted rare disease patient registry at the local and national levels. This data can potentially be accessed by multiple stakeholders for collaborative research and to enhance healthcare management for rare diseases.

Expanded Newborn Screening for Inborn Errors of Metabolism in Hong Kong: Results and Outcome of a 7 Year Journey.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism.

In this study, we evaluated the implementation of a second-tier genetic screening test using an amplicon-based next-generation sequencing (NGS) panel in our laboratory during the period of 1 September 2021 to 31 August 2022 for the newborn screening (NBS) of six conditions for inborn errors of metabolism: citrullinemia type II (MIM #605814), systemic primary carnitine deficiency (MIM #212140), glutaric acidemia type I (MIM #231670), beta-ketothiolase deficiency (#203750), holocarboxylase synthetase deficiency (MIM #253270) and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MIM # 246450). The custom-designed NGS panel can detect sequence variants in the relevant genes and also specifically screen for the presence of the hotspot variant IVS16ins3kb of SLC25A13 by the copy number variant calling algorithm. Genetic second-tier tests were performed for 1.8% of a total of 22,883 NBS samples. The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. The confirmed true positive cases were citrullinemia type II (n = 2) and systemic primary carnitine deficiency (n = 1). The false positives were later confirmed to be carrier of citrullinemia type II (n = 2), carrier of glutaric acidemia type I (n = 1) and carrier of systemic primary carnitine deficiency (n = 1). There were no false negatives reported. The incorporation of a second-tier genetic screening test by NGS greatly enhanced our program's performance with 5-working days turn-around time maintained as before. In addition, early genetic information is available at the time of recall to facilitate better clinical management and genetic counseling.

Hyperammonemia in a girl who inherited a likely pathogenic variant of the ornithine transcarbamylase gene from her asymptomatic father-A peculiar pattern of X-linked recessive inheritance.

A three-year-old Chinese girl presented with hyperammonemia was diagnosed biochemically and genetically (heterozygous for a novel likely pathogenic missense variant c.476T>A) as having ornithine transcarbamylase (OTC) deficiency, a rare X-linked recessive urea cycle disorders. Extensive family genetic screening eventually revealed paternal gonadosomatic mosaicism.

Case Report: The first familial hCG syndrome in a Chinese family.

Familial hCG syndrome is a rare and benign cause of elevated serum beta human chorionic gonadotropin (hCG). We present here a case of familial hCG syndrome diagnosed in a Hong Kong Chinese family, which we believe to be the first reported in Chinese. A 38-year-old woman presented with incidental finding of persistently elevated hCG, analytically confirmed both in urine and blood. Extensive radiological and biochemical work-up were performed but were negative for pregnancy and malignancy. Testing of another asymptomatic family member revealed unexplained elevation of serum hCG, confirming the diagnosis of familial hCG syndrome. Knowledge and awareness of this entity among clinicians are important to avoid unnecessary investigations and treatment in affected families.

Determination of cerebrospinal fluid adenosine deaminase activity cut-off for the diagnosis of tuberculous meningitis in Hong Kong.

AIMS: Tuberculous meningitis (TBM) is a severe infection which may lead to serious complication and mortality. Prompt diagnosis and treatment are essential. There is a need for a simple and fast laboratory test to differentiate TBM from other causes. METHODS: Retrospective review was conducted for cerebrospinal fluid adenosine deaminase (CSF-ADA) activity which was measured at the Chemical Pathology Laboratory of Princess Margaret Hospital, the sole centre providing such service in Hong Kong, for 51 patients with suspected meningitis from nine local hospitals between June 2014 and July 2017. TBM diagnosis was defined by positive culture and/or nucleic acid amplification test result of Mycobacterium tuberculosis complex in CSF. RESULTS: CSF-ADA activity was significantly higher in the TBM group (8.6±2.1 IU/L, n=8) than that of the non-TBM group (2.8±5.9 IU/L, n=43). The optimal clinical cut-off of 5.1 U/L for TBM diagnosis in our laboratory yielded 100% sensitivity, 91% specificity, positive likelihood ratio of 10.8 and negative likelihood ratio of 0. In rare circumstance, false elevation may be seen in non-tuberculous cause, such as central nervous system lymphoma and fungal infection. CONCLUSIONS: We recommend the use of CSF-ADA activity, which is a simple, fast and robust test for early differentiation of TBM from other causes, to facilitate timely initiation of antituberculous treatment and potentially improve patients' outcome.