Rulai Yang

Newborn screening (NBS) is a critical component of the three-tiered prevention strategy for birth defects, reducing congenital disorder burden and improving long-term child health outcomes. Over the past 45 years, NBS in China has evolved into a nationwide quality-controlled network driven by policy support and technological advances. Currently, phenylketonuria and congenital hypothyroidism are included in universal NBS across the country, and several provinces have expanded to encompass congenital adrenal hyperplasia, glucose-6-phosphate dehydrogenase deficiency, and additional inherited metabolic disorders identified through tandem mass spectrometry. The application of next-generation sequencing and other technologies has further enhanced detection capacity and expanded detectable disease spectra. Meanwhile, the National Quality Management System for NBS (QMS-NBS) has realized the visualization and standardization of screening quality and performance. Despite these advances, challenges remain, including regional disparities, inadequate follow-up, and long-term management. This review summarizes the historical evolution and policy framework of NBS in China, outlines the development of screening institutions, the spectrum and incidence of screened disorders, advances in detection technologies, and the establishment of QMS-NBS. It also highlights future priorities: expanding screened conditions, strengthening follow-up and long-term care, promoting regional equity, and advancing novel technologies to improve child health and foster precision public health.

Background: The red cell distribution width-to-albumin ratio is a novel composite biomarker reflecting systemic inflammation and nutritional status. This study aimed to evaluate the association between the red cell distribution width-to-albumin ratio and the prevalence of osteoarthritis as well as long-term mortality risk among US adults, thereby exploring the potential value of the red cell distribution width-to-albumin ratio as a marker for osteoarthritis risk assessment and prognostic evaluation. Methods: Data were obtained from the National Health and Nutrition Examination Survey in the United States, covering the years 2003–2016 and comprising 31,994 adult participants. The association between the red cell distribution width-to-albumin ratio and the prevalence of osteoarthritis was examined using logistic regression models. Additionally, prospective Cox regression models were used to evaluate the relationship between the red cell distribution width-to-albumin ratio and all-cause and cardiovascular mortality among patients with osteoarthritis. The models were adjusted for multiple important covariates, including age, sex, body mass index, race, lifestyle factors (such as smoking and alcohol consumption), and chronic comorbidities (such as diabetes, hypertension, and cardiovascular disease history). Restricted cubic spline analysis was performed to examine the nonlinear association between red cell distribution width-to-albumin ratio and mortality risk. Kaplan–Meier survival analysis, subgroup analyses, and interaction assessments were conducted to validate the robustness of the results. Results: Among 31,994 participants, 3150 were identified with osteoarthritis; of these, 3147 had follow-up records and were included in the survival analysis. After adjustment for key covariates, red cell distribution width-to-albumin ratio remained positively associated with the prevalence of osteoarthritis (adjusted odds ratio = 1.13, 95% confidence interval: 1.01–1.25). Compared with the lowest quartile (Q1), the highest quartile (Q4) of red cell distribution width-to-albumin ratio was significantly associated with an increased prevalence of osteoarthritis (odds ratio = 1.27, 95% confidence interval: 1.09–1.48). During a median follow-up of 92 months, higher red cell distribution width-to-albumin ratio significantly predicted all-cause mortality (hazard ratio = 2.11, 95% confidence interval: 1.74–2.56) and cardiovascular mortality (hazard ratio = 2.08, 95% confidence interval: 1.68–2.58) among patients with osteoarthritis. Further analysis revealed a significant nonlinear J-shaped association between red cell distribution width-to-albumin ratio and all-cause mortality risk among patients with osteoarthritis, with a threshold value of 2.84, above which mortality risk increased markedly (p < 0.05). Conclusions: This study suggests that the red cell distribution width-to-albumin ratio is associated with osteoarthritis prevalence and mortality risk among adults with osteoarthritis. Red cell distribution width-to-albumin ratio may represent a potential risk marker for osteoarthritis-related risk assessment and prognostic evaluation.

Background: Tandem mass spectrometry (MS/MS) has been progressively integrated into newborn screening (NBS) in China over the past decades. However, variations exist in screening strategies, coverage and support systems across different regions. This study aims to investigate the current status of MS/MS-based NBS across China, providing insights into progress and future challenges. Methods: This retrospective investigation included 42 634 198 newborns screened at 267 NBS centres across 28 provinces in China between 2017 and 2021. These centres were divided into Eastern, Central and Western regions based on geographical location and economic development level. Data analysis focuses on screening rate, suspected positive rate, incidence and diagnostic efficiency of MS/MS-based NBS across these regions. Results: Over the 5-year study period, the nationwide MS/MS-based screening rate increased consistently from 36.93% in 2017 to 49.93% in 2021, with the prominent trend in the Central region. The suspected positive rates of amino acid metabolism disorders, organic acid metabolism disorders and fatty acid oxidation disorders showed a notable upward trend. In 2021, the nationwide incidences of amino acid metabolism disorders, organic acid metabolism disorders and fatty acid oxidation disorders were 15.34, 12.59 and 13.18 per 100 000 live births, respectively. Despite challenges, the diagnostic time for organic acid metabolism disorders in the Western region significantly improved, and similar ascending trends were observed for fatty acid oxidation disorders in most regions. Conclusion: Our findings highlight the remarkable progress of MS/MS in China’s NBS and its indispensable role as the primary method. Continued advancement will be key to improving health outcomes and safeguarding the well-being of newborns nationwide.

Newborn screening (NBS) for thyroid dysfunction traditionally relies on physician interpretation of laboratory results, which can be subjective and labor-intensive. In this study, a two-phase machine learning framework was developed to automate the diagnostic process. Based on screening data from 5,406 newborns collected from Children’s Hospital ZheJiang University School of Medicine, 7 thyroid-related indicators were analyzed. In the first phase, a Random Forest model was trained to distinguish healthy individuals from those with thyroid dysfunction, achieving an AUC of 0.9914, a sensitivity of 98.57%, and a specificity of 98.60%. In the second phase, diseased samples were further classified into congenital hypothyroidism (CH), elevated TSH, or elevated TSH requiring medication, with a stacking ensemble model achieving a macro AUC of 0.9696 and an accuracy of 93.75%. SHAP value analysiswas used both for feature selection and interpretability, identifying TSH, FT4, and T4 as the most informative biomarkers. A large language model (LLM) was integrated to assist cases with low model confidence. The system was deployed through a web-based interface, enabling automatic diagnosis based on input laboratory indicators.

Background: Newborn screening (NBS) for severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and spinal muscular atrophy (SMA) enables early diagnosis and intervention, significantly improving patient outcomes. Advances in real-time polymerase chain reaction (PCR) technology have been instrumental in facilitating their inclusion in NBS programs. Methods: We employed multiplex real-time PCR to simultaneously detect T-cell receptor excision circles (TRECs), kappa-deleting recombination excision circles (KRECs), and the absence of the survival motor neuron (SMN) 1 gene in dried blood spots from 103,240 newborns in Zhejiang Province, China, between July 2021 and December 2022. Results: Of all the samples, 122 were requested further evaluation. After flow cytometry evaluation and/or genetic diagnostics, we identified one patient with SCID, two patients with XLA, nine patients with SMA [one of whom also had Wiskott–Aldrich Syndrome (WAS)], and eight patients with other medical conditions. The positive predictive values (PPVs) of NBS for SCID, XLA, and SMA were 2.44%, 2.78%, and 100%, respectively. The estimated prevalence rates in the Chinese population were 1 in 103,240 for SCID, 1 in 51,620 for XLA, and 1 in 11,471 for SMA. Conclusion: This study represents the first large-scale screening in mainland China using a TREC/KREC/SMN1 multiplex assay, providing valuable epidemiological data. Our findings suggest that this multiplex assay is an effective screening method for SCID, XLA, and SMA, potentially supporting the universal implementation of NBS programs across China. Graphical

Fatty acid oxidation disorders (FAODs) are a group of rare, autosomal recessive, metabolic disorders with clinical symptoms from mild types of fatigue, muscle weakness to severe types of hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis, especially during prolonged fasting, exercise, and illness. There are eleven diseases caused by thirteen FAOD genes (SLC22A5, ETFDH, ETFA, ETFB, SLC25A20, ACADS, ACADM, ACADVL, ACAT1, CPT1A, CPT2, HADHA, and HADHB) which are specific enzymes or transport proteins involved in the mitochondrial catabolism of fatty acids. We built the LOVD database for FAODs focused on the Chinese population, in which we recorded all the reported variants by literature peer review. In addition, the unpublished variant data of patients from Zhejiang province were also incorporated into the database. Currently, a total of 538 unique variants have been recorded. We also compared the incidence of high-frequency variants of certain FAOD genes among different populations. The database would provide the guidance for genetic screening of Chinese patients.

Background: Newborn screening (NBS) has been implemented for neonatal inborn disorders using various technology platforms, but false-positive and false-negative results are still common. In addition, target diseases of NBS are limited by suitable biomarkers. Here we sought to assess the feasibility of further improving the screening using next-generation sequencing technology. Methods: We designed a newborn genetic sequencing (NBGS) panel based on multiplex PCR and next generation sequencing to analyze 134 genes of 74 inborn disorders, that were validated in 287 samples with previously known mutations. A retrospective cohort of 4986 newborns was analyzed and compared with the biochemical results to evaluate the performance of this panel. Results: The accuracy of the panel was 99.65% with all samples, and 154 mutations from 287 samples were 100% detected. In 4986 newborns, a total of 113 newborns were detected with biallelic or hemizygous mutations, of which 36 newborns were positive for the same disorder by both NBGS and conventional NBS (C-NBS) and 77 individuals were NBGS positive/C-NBS negative. Importantly, 4 of the 77 newborns were diagnosed currently including 1 newborn with methylmalonic acidemia, 1 newborn with primary systemic carnitine deficiency and 2 newborns with Wilson’s disease. A total of 1326 newborns were found to be carriers with an overall carrier rate of 26.6%. Conclusion: Analysis based on next generation sequencing could effectively identify neonates affected with more congenital disorders. Combined with C-NBS, this approach may improve the early and accurate identification of neonates with inborn disorders. Our study lays the foundation for prospective studies and for implementing NGS-based analysis in NBS.

Congenital heart disease (CHD) is the most common of congenital cardiovascular malformations associated with birth defects, and it results in significant morbidity and mortality worldwide. The classification of CHD is still elusive owing to the complex pathogenesis of CHD. Advances in molecular medicine have revealed the genetic basis of some heart anomalies. Genes associated with CHD might be modulated by various epigenetic factors. Thus, the genetic and epigenetic factors are gradually accepted as important triggers in the pathogenesis of CHD. However, few literatures have comprehensively elaborated the genetic and epigenetic mechanisms of CHD. This review focuses on the etiology of CHD from genetics and epigenetics to discuss the role of these factors in the development of CHD. The interactions between genetic and epigenetic in the pathogenesis of CHD are also elaborated. Chromosome abnormalities and gene mutations in genetics, and DNA methylations, histone modifications and on-coding RNAs in epigenetics are summarized in detail. We hope the summative knowledge of these etiologies may be useful for improved diagnosis and further elucidation of CHD so that morbidity and mortality of children with CHD can be reduced in the near future.