A meta-analysis of tissue microbial biomarkers for recurrence and metastasis in multiple cancer types.

Background. Local recurrence and distant metastasis are the main causes of death in patients with cancer. Only considering species abundance changes when identifying markers of recurrence and metastasis in patients hinders finding solutions.Hypothesis. Consideration of microbial abundance changes and microbial interactions facilitates the identification of microbial markers of tumour recurrence and metastasis.Aim. This study aims to simultaneously consider microbial abundance changes and microbial interactions to identify microbial markers of recurrence and metastasis in multiple cancer types.Method. One thousand one hundred and six non-RM (patients without recurrence and metastasis within 3 years after initial surgery) tissue samples and 912 RM (patients with recurrence or metastasis within 3 years after initial surgery) tissue samples representing 11 cancer types were collected from The Cancer Genome Atlas (TCGA).Results. Tumour tissue bacterial composition differed significantly among 11 cancers. Among them, the tissue microbiome of four cancers, head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD) and uterine corpus endometrial carcinoma (UCEC), showed relatively good performance in predicting recurrence and metastasis in patients, with areas under the receiver operating characteristic curve (AUCs) of 0.78, 0.74, 0.91 and 0.93, respectively. Considering both species abundance changes and microbial interactions for the four cancers, a combination of nine genera (Niastella, Schlesneria, Thioalkalivibrio, Phaeobacter, Sphaerotilus, Thiomonas, Lawsonia, Actinobacillus and Spiroplasma) performed best in predicting patient survival.Conclusion. Taken together, our results imply that comprehensive consideration of microbial abundance changes and microbial interactions is helpful for mining bacterial markers that carry prognostic information.

Increased incidence of congenital hypothyroidism in China: An analysis of 119 million screened newborns.

Despite the lack of nationwide epidemiological studies, congenital hypothyroidism (CH) incidence in China has increased. We aimed to evaluate the trends of CH and the possible reasons behind them. Data from screened newborns from the Chinese Newborn Screening Information System from 2012 to 2019 was collected. We applied the Bayesian hierarchical Poisson regression model and meta-analysis to estimate incidence or proportion over the years. The estimated CH incidence increased from 4.01 per 10,000 births in 2012 to 5.77 per 10,000 births in 2019. The average annual growth rate (ARG) of CH incidence for all provinces varied from 0.59 to 20.96%. The most rapid rise in incidence was observed in cases with an initial thyroid stimulating hormone (TSH) concentration of < 10 mIU/L. The meta-analysis results showed that the proportion of permanent CH increased by 0.024% (95%CI: 0.011%, 0.037%) annually. Each 1 mIU/L decrease in TSH cutoff value was associated with a 2.96% increase in CH incidence. In the same period, the proportion of premature CH cases increased from 6.60 to 9.10%, which was much higher than the increase in preterm births. A significant relationship was not found between provincial growth rates in screening coverage and provincial baseline incidences of CH.  Conclusion: CH incidence has substantially increased in China. The slight adjustment of the TSH cutoff value and increasing preterm birth rate contribute to such a trend; however, the contribution is limited. What is Known: • An uptrend in congenital hypothyroidism (CH) incidence has been reported in many European and American countries in the last two decades; however, no studies have been conducted in China to explain the increased CH incidence. • We provide a detailed epidemiological report on the trends of CH during 2012-2019 in China, with an attempt to explore the reasons behind it. What is New: • This first-ever national-wide epidemiological report in China showed an uptrend in CH incidence with variations over regions and CH subtypes. The mild lowering of TSH cutoff values and the increasing preterm birth rate contributed to this uptrend.

Global prevalence of congenital hypothyroidism among neonates from 1969 to 2020: a systematic review and meta-analysis.

Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy.  Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.

Maternal Exposure to PM2.5 and the Risk of Congenital Heart Defects in 1.4 Million Births: A Nationwide Surveillance-Based Study.

BACKGROUND: Evidence remains limited about the association of maternal exposure to ambient fine particulate matter (airborne particles with an aerodynamic diameter ≤2.5 µm [PM2.5]) with fetal congenital heart defects (CHDs) in highly polluted regions, and few studies have focused on preconception exposure. METHODS: Using a nationwide surveillance-based case-control design in China, we examined the association between maternal exposure to PM2.5 during periconception (defined as 3 months before conception until 3 months into pregnancy) and risk of CHD in offspring. The study included 1 434 998 births involving 7335 CHDs from 2014 through 2017 on the basis of the National Population-Based Birth Defects Surveillance System, covering 30 provinces, municipalities, or municipal districts in China. We assigned maternal PM2.5 exposure during the periconception period to each participant using satellite-based PM2.5 concentrations at 1-km spatial resolution. Multilevel logistic regression models were used to calculate the multivariable-adjusted odds ratio and 95% CI for CHDs in offspring associated with maternal PM2.5 exposure, and the exposure-response association was investigated using restricted cubic spline analysis. Subgroup or sensitivity analyses were conducted to identify factors that may modify the association. RESULTS: The average maternal exposure to PM2.5 levels across all participants was 56.51 µg/m3 (range, 10.95 to 182.13 µg/m3). For each 10 µg/m³ increase in maternal PM2.5 exposure, the risk of CHDs in offspring was increased by 2% (odds ratio, 1.02 [95% CI, 1.00 to 1.05]), and septal defect was the most influenced subtype (odds ratio, 1.04 [95% CI, 1.01 to 1.08]). The effect of PM2.5 on CHD risk was more pronounced during the preconception period. Mothers <35 years of age, those living in northern China, and those living in low-income areas were more susceptible to PM2.5 exposure than their counterparts (all P<0.05). PM2.5 exposure showed a linear association with total CHDs or specific CHD types. CONCLUSIONS: High maternal PM2.5 exposure, especially during the preconception period, increases risk of certain types of CHD in offspring. These findings are useful for CHD prevention and highlight the public health benefits of improving air quality in China and other highly polluted regions.

Non-invasive prenatal testing for the detection of trisomies 21, 18, and 13 in pregnant women with various clinical indications: A multicenter observational study of 1,854,148 women in China.

OBJECTIVE: This study aimed to evaluate the performance of noninvasive prenatal testing (NIPT) for detecting three common trisomies (T21, T18, and T13) in pregnant women with diverse clinical indications. METHODS: Frequencies of NIPT, of high chance of having one of the three trisomies, and of confirmed trisomies were determined for women with each of seven clinical indications in a national cross-sectional survey of approximately 300 prenatal diagnosis centers. Data were collected for the period from October 1, 2016 to September 30, 2018 using the Prenatal Diagnosis Technology Management On-line Information System. The performance of NIPT for detecting the three trisomies in pregnant women with different clinical indications was assessed in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value, and the corresponding 95% confidence intervals. RESULTS: A total of 5766 true positive cases for T21, T18, and T13 were detected among 1,854,148 samples, giving an overall detection rate of 0.31% (95% CI: 0.30%-0.32%). Most positive cases were associated with "NT thickening" (1.18%) and "advanced maternal age" (0.51%). The detection sensitivities of NIPT were 99.60% for T21, 99.14% for T18, and 100% for T13, while the corresponding specificities were 99.90%, 99.94%, and 99.95%. The corresponding PPVs were 69.77%, 47.24%, and 22.36%. NIPT showed high sensitivity and specificity, regardless of clinical indication. In contrast, PPV for three trisomies varied widely between 9.09% and 66.46% depending on the clinical indication. Across seven clinical indications, PPV ranged from 50.62% to 73.09% for T21, 20.00%-58.33% for T18, and 4.17%-47.37% for T13. The highest PPVs were 73.09% for T21 in pregnancies involving "advanced maternal age", 58.33% for T18 in pregnancies with "NT thickening", and 47.37% for T13 in pregnancies with "NT thickening". CONCLUSIONS: NIPT shows high sensitivity and specificity for detecting T21, T18, and T13 in pregnant women with different clinical indications. However, PPV depends strongly on clinical indication, highlighting the need to strengthen education and genetic counseling about prenatal screening.

Biomarkers for isolated congenital heart disease based on maternal amniotic fluid metabolomics analysis.

INTRODUCTION: Congenital heart disease (CHD) is one of the most prevalent birth defects in the world. The pathogenesis of CHD is complex and unclear. With the development of metabolomics technology, variations in metabolites may provide new clues about the causes of CHD and may serve as a biomarker during pregnancy. METHODS: Sixty-five amniotic fluid samples (28 cases and 37 controls) during the second and third trimesters were utilized in this study. The metabolomics of CHD and normal fetuses were analyzed by untargeted metabolomics technology. Differential comparison and randomForest were used to screen metabolic biomarkers. RESULTS: A total of 2472 metabolites were detected, and they were distributed differentially between the cases and controls. Setting the selection criteria of fold change (FC) ≥ 2, P value < 0.01 and variable importance for the projection (VIP) ≥ 1.5, we screened 118 differential metabolites. Within the prediction model by random forest, PE(MonoMe(11,5)/MonoMe(13,5)), N-feruloylserotonin and 2,6-di-tert-butylbenzoquinone showed good prediction effects. Differential metabolites were mainly concentrated in aldosterone synthesis and secretion, drug metabolism, nicotinate and nicotinamide metabolism pathways, which may be related to the occurrence and development of CHD. CONCLUSION: This study provides a new database of CHD metabolic biomarkers and mechanistic research. These results need to be further verified in larger samples.

Bacterial biomarkers capable of identifying recurrence or metastasis carry disease severity information for lung cancer.

Background: Local recurrence and distant metastasis are the main causes of death in patients with lung cancer. Multiple studies have described the recurrence or metastasis of lung cancer at the genetic level. However, association between the microbiome of lung cancer tissue and recurrence or metastasis remains to be discovered. Here, we aimed to identify the bacterial biomarkers capable of distinguishing patients with lung cancer from recurrence or metastasis, and how it related to the severity of patients with lung cancer. Methods: We applied microbiome pipeline to bacterial communities of 134 non-recurrence and non-metastasis (non-RM) and 174 recurrence or metastasis (RM) samples downloaded from The Cancer Genome Atlas (TCGA). Co-occurrence network was built to explore the bacterial interactions in lung cancer tissue of RM and non-RM. Finally, the Kaplan-Meier survival analysis was used to evaluate the association between bacterial biomarkers and patient survival. Results: Compared with non-RM, the bacterial community of RM had lower richness and higher Bray-Curtis dissimilarity index. Interestingly, the co-occurrence network of non-RM was more complex than RM. The top 500 genera in relative abundance obtained an area under the curve (AUC) of 0.72 when discriminating between RM and non-RM. There were significant differences in the relative abundances of Acidovorax, Clostridioides, Succinimonas, and Shewanella, and so on between RM and non-RM. These biomarkers played a role in predicting the survival of lung cancer patients and were significantly associated with lung cancer stage. Conclusion: This study provides the first evidence for the prediction of lung cancer recurrence or metastasis by bacteria in lung cancer tissue. Our results highlights that bacterial biomarkers that distinguish RM and non-RM are also associated with patient survival and disease severity.

Identifying cancer tissue-of-origin by a novel machine learning method based on expression quantitative trait loci.

Cancer of unknown primary (CUP) refers to cancer with primary lesion unidentifiable by regular pathological and clinical diagnostic methods. This kind of cancer is extremely difficult to treat, and patients with CUP usually have a very short survival time. Recent studies have suggested that cancer treatment targeting primary lesion will significantly improve the survival of CUP patients. Thus, it is critical to develop accurate yet fast methods to infer the tissue-of-origin (TOO) of CUP. In the past years, there are a few computational methods to infer TOO based on single omics data like gene expression, methylation, somatic mutation, and so on. However, the metastasis of tumor involves the interaction of multiple levels of biological molecules. In this study, we developed a novel computational method to predict TOO of CUP patients by explicitly integrating expression quantitative trait loci (eQTL) into an XGBoost classification model. We trained our model with The Cancer Genome Atlas (TCGA) data involving over 7,000 samples across 20 types of solid tumors. In the 10-fold cross-validation, the prediction accuracy of the model with eQTL was over 0.96, better than that without eQTL. In addition, we also tested our model in an independent data downloaded from Gene Expression Omnibus (GEO) consisting of 87 samples across 4 cancer types. The model also achieved an f1-score of 0.7-1 depending on different cancer types. In summary, eQTL was an important information in inferring cancer TOO and the model might be applied in clinical routine test for CUP patients in the future.

Lung Cancer Stage Prediction Using Multi-Omics Data.

Lung cancer is one of the leading causes of cancer death. Patients with early-stage lung cancer can be treated by surgery, while patients in the middle and late stages need chemotherapy or radiotherapy. Therefore, accurate staging of lung cancer is crucial for doctors to formulate accurate treatment plans for patients. In this paper, the random forest algorithm is used as the lung cancer stage prediction model, and the accuracy of lung cancer stage prediction is discussed in the microbiome, transcriptome, microbe, and transcriptome fusion groups, and the accuracy of the model is measured by indicators such as ACC, recall, and precision. The results showed that the prediction accuracy of microbial combinatorial transcriptome fusion analysis was the highest, reaching 0.809. The study reveals the role of multimodal data and fusion algorithm in accurately diagnosing lung cancer stage, which could aid doctors in clinics.

A systematic review of newborn and childhood hearing screening around the world: comparison and quality assessment of guidelines.

BACKGROUND: This study aimed to assess the quality of global guidelines or consensus statements for newborn and childhood hearing screening, as well as to compare various guidelines between other countries and China. METHODS: A PROSPERO registered systematic review (number CRD42021242198) was conducted. Multiple electronic databases and government websites including PubMed, EMBASE, Web of Science, CENTRAL, Cochrane Library, and BMJ Best Practice were searched from inception until May 2021. The latest national and international guidelines, consensus statements, technical specifications, and recommendations regarding newborn or childhood hearing screening that were published in Chinese or English medical journals or elsewhere with the full version available online. The following information was extracted independently by two reviewers for comparative analysis: titles, authors, publication year, country, the source organization, and main key recommendations using systems for assigning the level of evidence and strength of recommendations. The quality of the guidelines was assessed by three independent reviewers using the Appraisal of Guidelines for Research and Evaluation, 2nd edition. Intraclass correlation coefficients (ICCs) were calculated to assess among-reviewer agreement. RESULTS: We assessed 15 newborn and 6 childhood hearing screening guidelines, respectively. Most newborn guidelines recommend the 1-3-6 guidelines and pre-discharge screening; however, the specific screening times differ. 93.33% of newborn hearing guidelines recommend "primary screening-re-screening-diagnosis-intervention" for well-babies while 73.33% of the guidelines recommend "initial screening-diagnosis-intervention" for newborns in neonatal intensive care unit (NICU); 33.33% of the newborn hearing guidelines recommended initial screening coverage of > 95% while 46.66% did not mention it. Further, 26.66% of the newborn hearing guidelines recommended a referral rate to diagnosis within 4% while 60% did not mention it. Regarding childhood hearing screening guidelines, the screening populations differed across guidelines (age range: 0-9 years); most guidelines recommend pediatric hearing screening for all preschoolers. Only 50% of the guidelines specify screening and re-screening techniques, including pure-tone hearing screening, OAE, tympanometry, and others. The "Clarity of Presentation" domain achieved the highest mean score, and the lowest was "Editorial Independence" both in newborn and childhood guidelines. Overall score of newborn hearing screening guidelines ranged from 3 (2018 Europe) to 7 (2019 America), with an average score of 5.33. Average score of childhood hearing screening guidelines was 4.78, with the score ranging from 4 (2017 England, 2012 Europe, 2016 WHO) to 6.67 (2011 America). ICC analysis revealed excellent agreement across 21 guidelines (> 0.75). CONCLUSIONS: These findings indicated newborn hearing screening guidelines had superior quality over childhood ones. Comparative analysis suggested that recommendations of the Chinese newborn and pediatric hearing screening protocols are consistent with the mainstream international opinion. Moreover, this analysis demonstrated that "Editorial Independence" and "Stakeholder Involvement" have the greatest opportunities for improvement. These results may help to advance the quality of hearing screening guidelines in clinical practice and guide evidence-based updates.

Whole-exome sequencing reveals novel candidate single nucleotide variations for preventing adverse effects of levonorgestrel implantation.

Aim: To identify novel genes associated with adverse effects of levonorgestrel (LNG) implants based on comparative whole-exome sequencing. Materials & methods: A cohort comprising 104 participants, including 52 controls and 52 women with LNG-related adverse effects, was recruited. Seven cases and eight controls were selected for whole-exome sequencing. We verified 13 single nucleotide variations (SNVs) related with integrin-mediated signaling pathway and cell proliferation using the MassARRAY platform. Results: Finally, we screened 49 cases and 52 controls for analyses. Two SNVs (rs7255721 and rs1042522) were located in ADAMTS10 and TP53, respectively, and significantly different between two groups. These two SNVs lead to changes in protein structure and physicochemical parameters. Conclusion: Here, we defined two pathogenic mutations related to adverse LNG effects.

Geographic variations in the incidence of congenital hypothyroidism in China: a retrospective study based on 92 million newborns screened in 2013-2018.

BACKGROUND: Although congenital hypothyroidism (CH) has been widely studied in Western countries, CH incidence at different administrative levels in China during the past decade remains unknown. This study aimed to update the incidence and revealed the spatial pattern of CH incidence in the mainland of China, which could be helpful in the planning and implementation of preventative measures. METHODS: The data used in our study were derived from 245 newborns screening centers that cover 30 provinces of the Chinese Newborn Screening Information System. Spatial auto-correlation was analyzed by Global Moran I and Getis-Ord Gi statistics at the provincial level. Kriging interpolation methods were applied to estimate a further detailed spatial distribution of CH incidence at city level throughout the mainland of China, and Kulldorff space scanning statistical methods were used to identify the spatial clusters of CH cases at the city level. RESULTS: A total of 91,921,334 neonates were screened from 2013 to 2018 and 42,861 cases of primary CH were identified, yielding an incidence of 4.66 per 10,000 newborns screened (95% confidence interval [CI]: 4.62-4.71). Neonates in central (risk ratio [RR] = 0.84, 95% CI: 0.82-0.85) and western districts (RR = 0.71, 95% CI: 0.69-0.73) had lower probability of CH cases compared with the eastern region. The CH incidence indicated a moderate positive global spatial autocorrelation (Global Moran I value = 0.394, P  < 0.05), and the CH cases were significantly clustered in spatial distribution. A most likely city-cluster (log-likelihood ratio [LLR] = 588.82, RR = 2.36, P  < 0.01) and 25 secondary city-clusters of high incidence were scanned. The incidence of each province and each city in the mainland of China was estimated by kriging interpolation, revealing the most affected province and city to be Zhejiang Province and Hangzhou city, respectively. CONCLUSION: This study offers an insight into the space clustering of CH incidence at provincial and city scales. Future work on environmental factors need to focus on the effects of CH occurrence.

Birth prevalence of tetrahydrobiopterin deficiency in China: data from the national newborn screening program, 2013-2019.

BACKGROUND: Tetrahydrobiopterin deficiency (BH4D), a less common form of hyperphenylalaninemia (HPA), can lead to severe developmental retardation if untreated. Little has been reported on the prevalence of BH4D among live births worldwide. This study examined its prevalence across China and between geographical areas within the country. METHODS: We analyzed data from the Chinese national screening program for HPA in newborns between 2013 and 2019. BH4D prevalence was examined by province, region and the entire country. Provincial-level prevalence was estimated from the number of confirmed BH4D cases and screened newborns, after adjusting for HPA-positive recall rate. Regional- and national-level prevalences were estimated by summing provincial-level prevalences after weighting them by the number of live births. A Poisson distribution was assumed in order to calculate 95% confidence intervals (CIs) for prevalence. RESULTS: Among 107,078,115 newborns screened for HPA in China, 380 with BH4D were identified, corresponding to a total prevalence of 3.8 per 1,000,000 live births. Prevalence was higher in eastern regions (5.9 per 1,000,000) and northern regions (4.1 per 1,000,000) of China than in southern regions (1.6 per 1,000,000) or northwestern regions (1.7 per 1,000,000). Across the entire country, 3.9% cases of HPA were diagnosed as BH4D, and this proportion reached as high as 15.1% in the southern part of the country. CONCLUSIONS: These first insights into BH4D prevalence across China suggest slightly higher prevalence than in other countries, and it varies substantially by region. More attention should be paid to early diagnosis and timely treatment of BH4D.

A Computational Framework to Identify Biomarkers for Glioma Recurrence and Potential Drugs Targeting Them.

Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes. Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers. Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit ß2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas. Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.

Incidence of inborn errors of metabolism detected by tandem mass spectrometry in China: A census of over seven million newborns between 2016 and 2017.

BACKGROUND: The incidence of inborn errors of metabolism varies widely across countries. Very few studies have analyzed the incidence of these disorders in Mainland China. We aimed to estimate the overall and disease-specific incidences of inborn errors of metabolism in Chinese newborns and investigate the geographical distribution of these disorders. METHODS: A national cross-sectional survey was conducted to investigate newborn inborn errors of metabolism screening by tandem mass spectroscopy in Mainland China between 2016 and 2017. A total of 246 newborn screening centers were surveyed using a standardized questionnaire. We examined the cumulative and disease-specific incidences of inborn errors of metabolism in Mainland China as a whole and in different geographical locations. RESULTS: Over 7 million newborns were screened and 2747 were diagnosed with inborn errors of metabolism, yielding an overall incidence of 38.69 per 100,000 births (95% confidence interval: 37.27-40.17). The most common disorders were amino acid disorders (17.14 per 100,000 births, 95% confidence interval: 16.21-18.13), followed by organic acid disorders (12.39 per 100,000 births, 95% confidence interval: 11.60-13.24) and fatty acid oxidation disorders (9.16 per 100,000 births, 95% confidence interval: 8.48-9.89). The overall and disease-specific incidence rates differed significantly across geographical locations (P < 0.001). CONCLUSIONS: The overall incidence of inborn errors of metabolism in Chinese newborns is relatively high. It is urgent to establish the recommended uniform screening panel for inborn errors of metabolism to guide the national and regional tandem mass spectroscopy newborn screening programs.

Association between prepregnancy body mass index and risk of congenital heart defects in offspring: an ambispective observational study in China.

BACKGROUND: Congenital heart defects (CHDs) are the most common birth defect around the world. Maternal prepregnancy obesity has been proposed as a risk factor of CHDs, but the relationship of CHD risk with over- and underweight is controversial, especially because body mass index (BMI) distribution differs between Asia and the West. The study aimed to examine the potential associations of maternal over- and underweight on risk of offspring CHDs. METHODS: An ambispective observational study involving 1206 fetuses with CHDs and 1112 fetuses without defects at seven hospitals in China was conducted. Standardized questionnaires were used to collect information on maternal prepregnancy weight and height, social demographic characteristics, living and occupational environments, and lifestyle behaviors. Univariate, multivariate and multilevel logistic regression as well as unrestricted cubic spline analysis were used to examine potential associations of prepregnancy BMI and offspring CHDs. RESULTS: Prepregnancy maternal underweight (BMI<18.5) or low average BMI (18.5 ≤ BMI<21.25) was associated with significantly higher risk of CHD in offspring than high average BMI (21.25 ≤ BMI<24.0): multilevel logistic regression indicated adjusted odds ratios of 1.53 (95%CI 1.13, 2.08) for underweight, 1.44 (95%CI 1.10, 1.89) for low average BMI and 1.29 (95%CI 0.84, 1.97) for overweight or obesity (BMI ≥ 24.0). Mothers with prepregnancy BMI < 21.25 were at greater risk of offspring with septal defects, while mothers with low average BMI were at greater risk of offspring with conotruncal defects and septal defects. CONCLUSIONS: Our findings suggest that underweight or low average BMI may be associated with higher risk of CHDs in offspring. Health professionals may wish to advise women planning to be pregnant to maintain or even gain weight to ensure adequate, balanced nutrition and thereby reduce the risk of CHDs in their offspring.

Newborn hearing screening coverage and detection rates of hearing impairment across China from 2008-2016.

BACKGROUND: Newborn hearing screening (NHS) can reduce the economic and social burden of hearing impairment. To track the progress of the goal set by the National Program of Action for Child Development (NPACD) and to estimate the detection rates of hearing impairment, the present study examined NHS coverage in 2008-2010 and 2016 and the detection of hearing impairment across China in 2016. METHODS: Licensed medical institutions across China were surveyed in 2012 and 2018 by the National Center for Birth Defects Monitoring of China to collect data for the 2008-2010 period and for 2016 on live births, initial screening rates (total and referral), secondary screening rates (total and referral), and rates of hearing impairment diagnosis among infants who were referred in the secondary screening. To calculate universal newborn hearing screening (UNHS) coverage, the number of newborns who received NHS within 4 weeks after birth was divided by the number of live births. The detection rate of hearing impairment was calculated by combining referral rates on primary and secondary screening with the rate of diagnosis. RESULTS: National UNHS coverage increased from 29.9% in 2008 to 86.5% in 2016, with different regions showing different increases. During this period, the number of provinces with UNHS coverage over 90.0% increased from 2 to 17, with UNHS coverage in 2016 being substantially higher in eastern provinces (93.1%) than in western provinces (79.4%). In 2016, the detection rate of hearing impairment across the country was 0.23% (95% CI 0.15-0.25%), and it varied from 0.17% in western provinces to 0.22% in central provinces and 0.28% in eastern provinces. The lowest rate was 0.02% in Heilongjiang Province and the highest rate was 0.63% in Hainan Province. CONCLUSIONS: National UNHS coverage increased substantially from 2008 to 2016, although provinces and regions still showed differences. The detection rate of infant hearing impairment in China is comparable to that in other countries. A national individual-level information system is urgently needed in China to facilitate the integration of screening, diagnosis and treatment of infant hearing impairment, which may also lead to a more accurate estimate of the detection rate.

Phenylketonuria incidence in China between 2013 and 2017 based on data from the Chinese newborn screening information system: a descriptive study.

OBJECTIVE: This study examines the incidence and spatial clustering of phenylketonuria (PKU) in China between 2013 and 2017. METHODS: Data from the Chinese Newborn Screening Information System were analysed to assess PKU incidence with 95% CIs by province, region and disease severity. Spatial clustering of PKU cases was analysed using global and local spatial autocorrelation analysis in the geographic information system. RESULTS: The database contained 4925 neonates with confirmed PKU during the study period, corresponding to an incidence of 6.28 (95% CI: 6.11 to 6.46) per 100 000 neonates screened. Incidence was highest in the provinces of Gansu, Ningxia and Qinghai, where it ranged from 19.00 to 28.63 per 100 000 neonates screened. Overall incidence was higher in the northern part of the country, where classical disease predominated, than in the southern part, where mild disease predominated. PKU cases clustered spatially (global Moran's I=0.3603, Z=5.3097, p<0.001), and local spatial autocorrelation identified four northern provinces as high-high clusters (Gansu, Qinghai, Ningxia and Shanxi). CONCLUSIONS: China shows an intermediate PKU incidence among countries, and incidence differs substantially among Chinese provinces and between northern and southern regions. Our results suggest the need to focus efforts on screening, diagnosing and treating PKU in high-incidence provinces.

Induced Abortion, Birth Control Methods, and Breast Cancer Risk: A Case-Control Study in China.

BACKGROUND: The association between induced abortion and birth control methods (including oral contraceptives and intrauterine devices) and breast cancer may vary among countries, due to the different usage and frequency of birth control methods and induced abortion among countries. A better understanding of this association may help in determining safer birth control methods for Chinese women. METHODS: A case-control study was conducted with a total of 794 cases and 805 controls. Standardized questionnaires were used to collect information on demographic characteristics, exposure to induced abortion, birth control methods, and other risk factors for breast cancer. Multivariate logistic regression was conducted to explore the association between birth control methods and breast cancer. RESULTS: Multivariate logistic regression analyses showed that having a history of medical abortions, ≥3 surgical abortions, or both medical and surgical abortions was associated with an increased risk of breast cancer in post-menopausal women (odds ratio [OR] 2.48; 95% confidence interval [CI], 1.14-5.40). Pre-menopausal women who had used intra-uterine devices (IUDs) for more than 20 years tended to have a lower breast cancer risk than other age-matched pre-menopausal women (OR 0.41; 95% CI, 0.25-0.68). Both pre-menopausal and post-menopausal women who had <20 years exposure to IUDs and those who had used two or more birth control methods (with the exception of women who used IUDs for more than 20 years) tended to have much higher breast cancer risk. CONCLUSION: The relationship between induced abortion and birth control methods and breast cancer was complex, though being exposed to induced abortion and two or more birth control methods in one's lifetime appeared to be risk factors for breast cancer in Chinese women.

[Combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases in neonates].

OBJECTIVE: To study the combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases (IMD). METHODS: A total of 3 381 samples ruled out of IMD by follow-up were randomly selected from 38 931 newborns who participated in the neonatal IMD screening during 2014-2016. The 3 381 neonates were categorized into seven groups according to their gestational age and birth weight: extremely preterm appropriate-for-gestational age (AGA) group (n=12), preterm small-for-gestational age (SGA) group (n=18), preterm AGA group (n=219), preterm large-for-gestational age (LGA) group (n=18), full-term SGA group (n=206), full-term AGA group (n=2 677), and full-term LGA group (n=231). Heel blood samples were collected from each group on postnatal days 3-7 after adequate breastfeeding. Levels of 17 key IMD-related metabolic indices in dried blood spots were measured using tandem mass spectrometry. Spearman′s correlation analysis was used to investigate the relationships between 17 IMD-related metabolic indices and their influencing factors, while covariance analysis was used to compare the metabolic indices between these groups. RESULTS: After adjusting the influencing factors such as physiological and pathological status, compared with the full-term AGA group, the extremely preterm AGA, preterm SGA, and preterm AGA groups had significantly reduced levels of leucine\isoleucine\hydroxyproline and valine (P<0.05); the preterm AGA group had a significantly decreased ornithine level (P<0.05); the extremely preterm AGA and preterm AGA groups had a significantly reduced proline level (P<0.05). Besides, the phenylalanine level in the extremely preterm AGA and preterm AGA groups, the methionine level in the preterm SGA group, and the tyrosine level in the preterm AGA group all significantly increased (P<0.05). The increased levels of free carnitine, acetylcarnitine, and propionylcarnitine were found in the preterm SGA and preterm AGA groups. The oleylcarnitine level also significantly increased in the preterm SGA group (P<0.05). Most carnitine indices showed significant differences between the SGA group and the AGA/LGA group in both preterm and full-term infants (P<0.05). CONCLUSIONS: Low gestational age and low birth weight may result in abnormal results in IMD screening. Therefore, gestational age and birth weight should be considered to comprehensively judge the abnormal results in IMD screening.