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Background Compositional data analysis (CoDA) is an emerging statistical framework and has been extended to microbiome, bulk RNA-seq, and cell type proportions in single-cell RNA-seq (scRNA-seq), which typically has 50–200 components. Here, we explore the high-dimensional application of CoDA (CoDA-hd) and its various log-ratio (LR) transformations to raw count matrix of scRNA-seq which has over 20,000 components (e.g., protein coding genes). scRNA-seq matrices are typically sparse and high-dimensional. Common approaches of normalization such as log-normalization may lead to suspicious findings as previously shown for trajectory inference. Although RNA-seq is compositional data by nature, the geometry of CoDA in high-dimensional simplex is not compatible with most downstream analyses of scRNA-seq which are based on Euclidean space. In this study, we attempted to explore: (1) CoDA adaptability to scRNA-seq; (2) handling of zero data: prior-log-normalization, imputation or with specific count addition scheme; (3) transformation to Euclidean space and compatibility with downstream analyses. Results Our results suggest that (1) the innovative count addition schemes (e.g., SGM) enable the application of CoDA to high dimensional sparse data (i.e., scRNA-seq); (2) log-normalized data could be transformed to CoDA LR representation; (3) CoDA LR transformations such as count-added centered-log-ratio (CLR) had some advantages in dimension reduction visualization, clustering, and trajectory inference in the tested real and simulated datasets. CLR provided more distinct and well-separated clusters in dimension reductions, improved the Slingshot trajectory inference, and eliminated the suspicious trajectory that was probably caused by the dropouts. Conclusions We therefore conclude that CoDA may be a preferred scale-free model to handle scRNA-seq data for these downstream tasks. Additionally, an R package ‘CoDAhd’ was developed for conducting CoDA LR transformations for high dimensional scRNA-seq data. The code for implementing CoDA-hd, along with some example datasets, are available at https://github.com/GO3295/CoDAhd .

Background Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. Methods From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. Results Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman’s rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. Conclusions In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients’ QOL.

In this prospective cross-sectional study on young premenopausal breast cancer patients, the objectives were to: determine the incidences of chemotherapy-related amenorrhea (CRA) and menopause (CRM); identify associated factors; and assess plasma levels of estradiol (E2) and follicular stimulating hormone (FSH) among patients who developed menopause. Eligibility criteria include Chinese stage I-III breast cancer patients, premenopausal, age ≤45 at breast cancer diagnosis, having received adjuvant chemotherapy, within 3-10 years after breast cancer diagnosis. Detailed menstrual history prior to and after adjuvant treatment was taken at study entry. Patients' background demographics, tumor characteristics and anti-cancer treatments were collected. The rates of CRA and CRM were determined. Analysis was conducted to identify factors associated with CRM. For postmenopausal patients, levels of E2 and FSH were analyzed. 286 patients were recruited; the median time from breast cancer diagnosis to study entry was 5.0 years. 255 patients (91.1%) developed CRA. Of these, 66.7% regained menstruation. At the time of study entry, 137 (48.9%) had developed CRM, amongst whom 84 were age ≤45. On multivariate analysis, age was the only associated factor. Among patients with CRM, the median FSH was 41.0 IU/L; this was significantly lower in those who were taking tamoxifen compared to those who were not (20.1 vs. 59.7 IU/L, p<0.0001). The E2 level was <40 pmol/L; there was no difference between those who were still on tamoxifen or not. After adjuvant chemotherapy, the majority of young Chinese breast cancer patients developed CRA; ~50% developed CRM, with 61% at age ≤45. Age at diagnosis is the only factor associated with CRM. FSH level may be affected by tamoxifen intake.

interferon signaling interacts with the pathway to drive hepatocellular carcinoma (HCC) progression and metastasis. , an interferon-inducible gene, is upregulated by the pathway and serves as a key factor for metabolic reprogramming to promote stem-like properties of cancer stem cells and tumor proliferation. In patients with resected HCC, upregulation showed an association with microvascular invasion, which is a proven risk factor for developing HCC metastasis. This clinical observation was compatible with preclinical findings. On the other hand, upregulation has been reported to confer poor prognosis in breast and gastric cancers. However, further clinical study of in HCC is lacking. As a result, we investigated the clinical implications of gene expression in HCC patients, in terms of its associations with survival, the presence of extra-hepatic metastasis, and other clinical manifestations. We studied 309 treatment-naïve HCC patients, as well as data from the TCGA and GTEx databases. gene expression was differentially upregulated in HCC tumors when compared to normal liver tissues ( < 0.01). Elevated mRNA levels in the blood and the presence of extra-hepatic metastasis were independent prognostic factors for poor overall survival (OS) ( < 0.01). The median OS of patients with high expression vs. low expression were 5.4 vs. 14.2 months, respectively ( < 0.01). A high mRNA level was significantly correlated with the presence of extra-hepatic metastasis, nutritional disturbance, and functional impairment after controlling for confounding clinical factors ( < 0.05). High gene expression is associated with poorer OS, the presence of extra-hepatic metastasis, and quality-of-life disturbances in HCC patients.

Pregnant women undergoing assisted reproductive technology (ART) have an increased risk of gestational diabetes mellitus (GDM), potentially linked to altered immune regulation, but the underlying circulating immune features remain unclear. Here we show an integrated single-cell transcriptomic, immune receptor repertoire, and plasma proteomic analysis of peripheral blood from 32 women with GDM and 31 normal pregnancies after ART. GDM is associated with increased proportions of CD8 + T cells and elevated plasma levels of CD6, CXCL5, MMP10, and 4E-BP1. Cytotoxic CD8 + T cell subsets display enhanced effector and cytotoxic activity, while B cells, monocytes, and natural killer cells exhibit activated phenotypes. Transcription factors from the FOS and JUN families and KLF6 are implicated in immune activation, accompanied by distinct T cell and B cell receptor repertoire features. The hypothesis-generating multi-omic results highlight potential therapeutic targets and offered insights for future research and management ART-associated pregnancy complications. Multimodal immune profiling of ART pregnancies reveals systemic immune hyperactivation in gestational diabetes, characterized by activated CD8⁺ T cells, altered immune repertoires, and inflammatory signaling driven by FOS/JUN and KLF6.

Adolescent idiopathic scoliosis (AIS) is widely recognized as a complex disorder with a strong genetic predisposition. In previous studies, a number of extracellular matrixes (ECMs) related genes have been duplicated as candidate genes for AIS. Matrilin-1 plays an important role in the organization of the ECM, and matrilin-1 gene ( MATN1 ) mutant mice showed similar phenotypes to scoliosis. We hypothesized that MATN1 was a candidate predisposition gene for AIS. A gene-based association study was conducted using seven tagging SNPs identified from the HapMap data. For initial screening, the seven tagSNPs were genotyped in 197 cases and 172 controls. Next, we validated any significant association in an additional sample of 222 cases and 288 controls. In addition, another 290 controls were genotyped to confirm the results. We found that allele G of rs1149048 was a significant predisposition allele of AIS ( P =0.0007, odds ratio (OR)=1.35 within 95% confidence interval (CI)=1.14–1.61), and individuals with genotype GG had a higher risk for AIS compared with AA+AG ( P =0.0001, OR=1.61 within 95% CI=1.25–2.08). Polymorphism of rs1149048 was also associated with curve severity in AIS patients. Also, a significantly higher maximum Cobb angle was found in patients with GG genotype ( P =0.002). We concluded that the tagSNP rs1149048 polymorphism in the MATN1 promoter region was associated with both susceptibility and disease progression in AIS.

Research into the mechanisms of human adaptation to the hypoxic environment of high altitude is of great interest to the fields of human physiology and clinical medicine. Recently, the gene EGLN1, from the hypoxia-inducible factor (HIF) pathway, was identified as being involved in the hypoxic adaptation of highland Andeans and Tibetans. Both highland Andeans and Tibetans have adapted to an extremely hypoxic habitat and less attention has been paid to populations living in normoxic conditions at sea level and mild-hypoxic environments of moderate altitude, thus, whether a common adaptive mechanism exists in response to quantitative variations of environmental oxygen pressure over a wide range of residing altitudes is unknown. Here, we first performed a genome-wide association study of 35 populations from the Human Genome Diversity-CEPH Panel who dwell at sea level to moderate altitude in Eurasia (N = 691; 0–2,500 m) to identify the genetic adaptation profile of normoxic and mild-hypoxic inhabitants. In addition, we systematically compared the results from the present study to six previously published genome-wide scans of highland Andeans and Tibetans to identify shared adaptive signals in response to quantitative variations of oxygen pressure. For normoxic and mild-hypoxic populations, the strongest adaptive signal came from the mu opioid receptor-encoding gene (OPRM1, 2.54 × 10−9), which has been implicated in the stimulation of respiration, while in the systematic survey the EGLN1-DISC1 locus was identified in all studies. A replication study performed with highland Tibetans (N = 733) and sea level Han Chinese (N = 748) confirmed the association between altitude and SNP allele frequencies in OPRM1 (in Tibetans only, P < 0.01) and in EGLN1-DISC1 (in Tibetans and Han Chinese, P < 0.01). Taken together, identification of the OPRM1 gene suggests that cardiopulmonary adaptation mechanisms are important and should be a focus in future studies of hypoxia adaptation. Furthermore, the identification of the EGLN1 gene from the HIF pathway suggests a common adaptive mechanism for Eurasian human populations residing at different altitudes with different oxygen pressures.

Background Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified. Methods Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3–10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients’ medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed. Results Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24–45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28–54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias. Conclusion Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted.

Background The interactions of multiple single nucleotide polymorphisms (SNPs) are highly hypothesized to affect an individual's susceptibility to complex diseases. Although many works have been done to identify and quantify the importance of multi-SNP interactions, few of them could handle the genome wide data due to the combinatorial explosive search space and the difficulty to statistically evaluate the high-order interactions given limited samples. Results Three comparative experiments are designed to evaluate the performance of MegaSNPHunter. The first experiment uses synthetic data generated on the basis of epistasis models. The second one uses a genome wide study on Parkinson disease (data acquired by using Illumina HumanHap300 SNP chips). The third one chooses the rheumatoid arthritis study from Wellcome Trust Case Control Consortium (WTCCC) using Affymetrix GeneChip 500K Mapping Array Set. MegaSNPHunter outperforms the best solution in this area and reports many potential interactions for the two real studies. Conclusion The experimental results on both synthetic data and two real data sets demonstrate that our proposed approach outperforms the best solution that is currently available in handling large-scale SNP data both in terms of speed and in terms of detection of potential interactions that were not identified before. To our knowledge, MegaSNPHunter is the first approach that is capable of identifying the disease-associated SNP interactions from WTCCC studies and is promising for practical disease prognosis.

Background Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2 , CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen. Methods Patients were monitored for adverse reactions throughout the treatment, then divided into “none or mild” (80 %) or “severe” (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 10 9 /L anytime during the treatment. DNA was extracted from patients’ peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis. Results Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P  = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P  = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 10 9 /L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia ( P  = 0.004). Conclusion Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene–environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.