Large-scale Population Analysis Research Articles

Testosterone levels increase following bariatric surgery - validation of preceding literature in a large-scale population analysis.

The effects of bariatric surgery on testosterone levels in men with obesity and hypogonadism have not been thoroughly explored yet. To investigate the possible effects of bariatric surgery on T levels in obese hypogonadal men by comparing T levels before and after surgery using a comprehensive claims database. The TriNetX US Collaborative Network database was used to identify men ages 18-80 who underwent a bariatric procedure and had a serum T value of<350ng/dL prior to surgery. Men who received testosterone therapy before/or after surgery were excluded. We conducted a retrospective self-matched cohort analysis to examine the difference in serum T levels before and after bariatric surgery. A sub-analysis was carried out to explore differences between men who reached eugonadal status or maintained low T levels following surgery. Descriptive statistics detailed sociodemographic and clinical characteristics, with continuous and categorical data compared using unpaired t-tests and chi-square analysis, respectively. Changes in T levels and body mass index (BMI) before and after surgery were compared using an unpaired t-test with a<0.05 set for significance. All analyses were conducted using the TriNetX platform which utilizes both Python and R software. The study analyzed 69 hypogonadal men who underwent bariatric surgery and had T levels assessed before and after the procedure. The mean (standard deviation) pre-surgery serum T level was 208±79ng/dL, which post-surgery increased to 371±164ng/dL, marking an average increase of 163±164ng/dL. Likewise, the mean (standard deviation) body mass index decreased from 42.9±9.0 to 38.8±5.7kg/m2. Post-surgery, 45% (31 men) achieved eugonadal status, while 55% (38 men) continued to have low T levels. A comparison between the post-surgery eugonadal cohort and the persistent low T cohort revealed that the former had higher pre-surgery serum T levels (235±71ng/dL vs. 184±80.4ng/dL, p=0.007), a higher pre-surgery body mass index (45.5±4.5kg/m2 vs. 41.1±11.5kg/m2, p=0.041), and a significantly greater reduction in body mass index post-surgery (7.3±7.2kg/m2 vs. 2.0±12.8kg/m2, p=0.04). Notably, the increase in T was significantly higher in the eugonadal cohort compared to the persistent low testosterone cohort (257±143ng/dL vs. 95±178ng/dL, p<0.0001). This study provides evidence of bariatric surgery's positive effect on serum T levels in obese men with baseline low T. Almost one out of two men with low T reached normal T levels after bariatric surgery. As the most comprehensive study to date, it validates and substantiates previous work suggesting that weight loss can improve T levels physiologically.

Haplotype-resolved T2T reference genomes for wild and domesticated accessions shed new insights into the domestication of jujube

Abstract Chinese jujube (Ziziphus jujuba Mill.) is one of the most important deciduous tree fruits in China, with substantial economic and nutritional value. Jujube was domesticated from its wild progenitor, wild jujube (Z. jujuba var. spinosa), and both have high medicinal value. Here we report the 767.81- and 759.24-Mb haplotype-resolved assemblies of a dry-eating ‘Junzao’ jujube (JZ) and a wild jujube accession (SZ), using a combination of multiple sequencing strategies. Each assembly yielded two complete haplotype-resolved genomes at the telomere-to-telomere (T2T) level, and ~81.60 and 69.07 Mb of structural variations were found between the two haplotypes within JZ and SZ, respectively. Comparative genomic analysis revealed a large inversion on each of chromosomes 3 and 4 between JZ and SZ, and numerous genes were affected by structural variations, some of which were associated with starch and sucrose metabolism. A large-scale population analysis of 672 accessions revealed that wild jujube originated from the lower reaches of the Yellow River and was initially domesticated at local sites. It spread widely and was then independently domesticated at the Shanxi–Shaanxi Gorge of the middle Yellow River. In addition, we identified some new selection signals regions on genomes, which are involved in the tissue development, pollination, and other aspects of jujube tree morphology and fertilization domestication. In conclusion, our study provides high-quality reference genomes of jujube and wild jujube and new insights into the domestication history of jujube.

Assessing population structure and migration patterns of wild boar (Sus scrofa) in Japan

Geographical wildlife patterns reflect historical range expansion and connectivity and provide insights into wildlife population management. In our large-scale phylogeographic population analysis of wild boars (Sus scrofa leucomystax) in Japan, we identified 15 clusters using 29 microsatellite markers, each structured within a range of approximately 200 km. This suggests that evolution was essentially driven by isolation by distance, and that the range of gene flow was limited. One cluster contained subpopulations located approximately 900 km apart, indicating the occurrence of past anthropogenic introductions. Moreover, we estimated effective migration to visualize the geographic genetic population diversity. This analysis identified six potential barriers, one of which involved large plains and mountainous areas in the Kanto region of eastern Japan. This barrier likely persisted in the two eastern clusters for an extended period, restricting migration to the neighboring areas. Overall, our study sheds light on the demographic history of wild boar in Japan, provides evidence of past anthropogenic introductions from distant areas, and highlights the importance of geographic barriers in shaping genetic diversity and population dynamics. This knowledge will be beneficial for forming informed wildlife management strategies toward the conservation of genetic integrity and ecological balance of wild boar populations in Japan.

Accurate and Efficient Photoeccentric Transit Modeling

A planet’s orbital eccentricity is fundamental to understanding the present dynamical state of a system and is a relic of its formation history. There is high scientific value in measuring the eccentricities of Kepler and Transiting Exoplanet Survey Satellite (TESS) planets given the sheer size of these samples and the diversity of their planetary systems. However, Kepler and TESS light curves typically only permit robust determinations of the planet-to-star radius ratio r, orbital period P, and transit midpoint t 0. Three other orbital properties, including the impact parameter b, eccentricity e, and argument of periastron ω, are more challenging to measure because they are all encoded in the light curve through subtle effects on a single observable—the transit duration T 14. In Gilbert et al., we showed that a five-parameter transit description {P, t 0, r, b, T 14} naturally yields unbiased measurements of r and b. Here, we build upon our previous work and introduce an accurate and efficient prescription to measure e and ω. We validate this approach through a suite of injection-and-recovery experiments. Our method agrees with previous approaches that use a seven-parameter transit description {P, t 0, r, b, ρ ⋆, e, ω}, which explicitly fits the eccentricity vector and mean stellar density. The five-parameter method is simpler than the seven-parameter method and is “future-proof” in that posterior samples can be quickly reweighted (via importance sampling) to accommodate updated priors and updated stellar properties. This method thus circumvents the need for an expensive reanalysis of the raw photometry, offering a streamlined path toward large-scale population analyses of the eccentricity from transit surveys.

Automatic localisation and per-region quantification of traumatic brain injury on head CT using atlas mapping

Rationale and objectivesTo develop a method for automatic localisation of brain lesions on head CT, suitable for both population-level analysis and lesion management in a clinical setting. Materials and methodsLesions were located by mapping a bespoke CT brain atlas to the patient’s head CT in which lesions had been previously segmented. The atlas mapping was achieved through robust intensity-based registration enabling the calculation of per-region lesion volumes. Quality control (QC) metrics were derived for automatic detection of failure cases. The CT brain template was built using 182 non-lesioned CT scans and an iterative template construction strategy. Individual brain regions in the CT template were defined via non-linear registration of an existing MRI-based brain atlas.Evaluation was performed on a multi-centre traumatic brain injury dataset (TBI) (n = 839 scans), including visual inspection by a trained expert. Two population-level analyses are presented as proof-of-concept: a spatial assessment of lesion prevalence, and an exploration of the distribution of lesion volume per brain region, stratified by clinical outcome. Results95.7% of the lesion localisation results were rated by a trained expert as suitable for approximate anatomical correspondence between lesions and brain regions, and 72.5% for more quantitatively accurate estimates of regional lesion load. The classification performance of the automatic QC showed an AUC of 0.84 when compared to binarised visual inspection scores. The localisation method has been integrated into the publicly available Brain Lesion Analysis and Segmentation Tool for CT (BLAST-CT). ConclusionAutomatic lesion localisation with reliable QC metrics is feasible and can be used for patient-level quantitative analysis of TBI, as well as for large-scale population analysis due to its computational efficiency (<2 min/scan on GPU).

Characteristics of lung metastasis in testicular cancer: A large-scale population analysis based on propensity score matching.

This study aims to systematically evaluate predictive factors for lung metastasis (LM) in patients with testicular cancer (TC) and to investigate cancer-specific survival (CSS) and overall survival (OS) of LM in TC patients based on a large population-cohort. A total of 10,414 patients diagnosed with TC during 2010-2015 were adopted from the Surveillance, Epidemiology, and End Results (SEER). After propensity score matching (PSM), 493 patients with LM were included for subsequent analysis. Univariate and multivariate logistic regression analyses were employed to identify risk factors, a nomogram was developed, and the receiver operating characteristic (ROC) curve was utilized to confirm the validation of the nomogram. Prognostic factors for OS and CSS among TC patients with LM were estimated via Cox proportional hazards models. Postmatching indicated that 11 parameters were successfully balanced between both groups (P > 0.05). After PSM, TC patients with LM presented an undesirable prognosis in both CSS and OS than those without LM (P < 0.001). The logistic regression model showed that tumor size; T stage; N stage; liver, brain, and bone metastases; and histology were positively associated with LM (P < 0.05). A nomogram was developed to predict diagnostic possibilities based on the independent risk variables, and the ROC curve verified the predictive capacity of the logistic regression model [area under the curve (AUC) = 0.910]. The selected variates in the nomogram can be predictive criteria for TC patients with LM. Brain metastasis, liver metastasis, and larger tumor size were prognostic factors for CCS and OS among TC patients with LM.

A Travel Mode Identification Framework Based on Cellular Signaling Data

The rapid development of telecommunication network has produced a large amount of spatial-temporal information of mobile phone users. GPS data are typically collected by smartphones apps, which are restricted to small samples of the population. Cellular signaling data (CSD) are usually collected by mobile network operators, which enables researchers to conduct travel behavior analysis of the entire population at a relatively low cost compared to GPS. However, extracting travel mode information from CSD is particularly challenging due to the noise data and low positioning accuracy. This paper proposes a travel mode identification framework based on CSD, which includes data cleansing and travel mode identification. In terms of data cleansing, oscillation sequence and drift data are mainly cleansed. For the oscillation sequence, this paper proposes a detection algorithm based on time window. For the drift data, this paper proposes a detection algorithm based on distance, velocity and frequency. In terms of travel mode identification, the task is divided into two dichotomous problems: motor and non-motor transport identification and public and private transport identification. Each dichotomous problem proposes an algorithm that does not rely on the ground truth dataset for model training. Finally, a ground truth dataset is constructed to verify all algorithms. The result shows that, in terms of data cleansing, the similarity between CSD after cleansing and the actual trajectory according to DTW improved by 101.13% on average. In terms of travel mode identification, the proposed method can achieve similar or even better accuracy than traditional supervised-learning algorithms (94% in motor and non-motor transport identification, 83.5% in public and private transport identification), which can be directly applied to large-scale population analysis scenarios.

Resolving the full spectrum of human genome variation using Linked-Reads.

Large-scale population analyses coupled with advances in technology have demonstrated that the human genome is more diverse than originally thought. To date, this diversity has largely been uncovered using short-read whole-genome sequencing. However, these short-read approaches fail to give a complete picture of a genome. They struggle to identify structural events, cannot access repetitive regions, and fail to resolve the human genome into haplotypes. Here, we describe an approach that retains long range information while maintaining the advantages of short reads. Starting from ∼1 ng of high molecular weight DNA, we produce barcoded short-read libraries. Novel informatic approaches allow for the barcoded short reads to be associated with their original long molecules producing a novel data type known as “Linked-Reads”. This approach allows for simultaneous detection of small and large variants from a single library. In this manuscript, we show the advantages of Linked-Reads over standard short-read approaches for reference-based analysis. Linked-Reads allow mapping to 38 Mb of sequence not accessible to short reads, adding sequence in 423 difficult-to-sequence genes including disease-relevant genes STRC, SMN1, and SMN2. Both Linked-Read whole-genome and whole-exome sequencing identify complex structural variations, including balanced events and single exon deletions and duplications. Further, Linked-Reads extend the region of high-confidence calls by 68.9 Mb. The data presented here show that Linked-Reads provide a scalable approach for comprehensive genome analysis that is not possible using short reads alone.

On Zebrafish Disease Models and Matters of the Heart.

Coronary artery disease (CAD) is the leading form of cardiovascular disease (CVD), which is the primary cause of mortality worldwide. It is a complex disease with genetic and environmental risk factor contributions. Reports in human and mammalian models elucidate age-associated changes in cardiac function. The diverse mechanisms involved in cardiac diseases remain at the center of the research interest to identify novel strategies for prevention and therapy. Zebrafish (Danio rerio) have emerged as a valuable vertebrate model to study cardiovascular development over the last few decades. The facile genetic manipulation via forward and reverse genetic approaches combined with noninvasive, high-resolution imaging and phenotype-based screening has provided new insights to molecular pathways that orchestrate cardiac development. Zebrafish can recapitulate human cardiac pathophysiology due to gene and regulatory pathways conservation, similar heart rate and cardiac morphology and function. Thus, generations of zebrafish models utilize the functional analysis of genes involved in CAD, which are derived from large-scale human population analysis. Here, we highlight recent studies conducted on cardiovascular research focusing on the benefits of the combination of genome-wide association studies (GWAS) with functional genomic analysis in zebrafish. We further summarize the knowledge obtained from zebrafish studies that have demonstrated the architecture of the fundamental mechanisms underlying heart development, homeostasis and regeneration at the cellular and molecular levels.

Diabetes: Quantifying genetic susceptibility in T1DM - implications for diagnosis after age 30.

Treatment of type 1 diabetes mellitus (T1DM) for individuals over the age of 30 years is often delayed. A recent large-scale population analysis used a genetic risk score to define T1DM in the first six decades of life, providing specific insights applicable to those >30 years of age.

A Tonoplast Sugar Transporter Underlies a Sugar Accumulation QTL in Watermelon.

How sugar transporters regulate sugar accumulation in fruits is poorly understood and particularly so for species storing high-concentration Suc. Accumulation of soluble sugars in watermelon (Citrullus lanatus) fruit, a major quality trait, had been selected during domestication. Still, the molecular mechanisms controlling this quantitative trait are unknown. We resequenced 96 recombinant inbred lines, derived from crossing sweet and unsweet accessions, to narrow down the size of a previously described sugar content quantitative trait locus, which contains a putative Tonoplast Sugar Transporter gene (ClTST2). Molecular and biochemical analyses indicated that ClTST2 encodes a vacuolar membrane protein, whose expression is associated with tonoplast uptake and accumulation of sugars in watermelon fruit flesh cells. We measured fruit sugar content and resequenced the genomic region surrounding ClTST2 in 400 watermelon accessions and associated the most sugar-related significant single-nucleotide polymorphisms (SNPs) to the ClTST2 promoter. Large-scale population analyses strongly suggest increased expression of ClTST2 as a major molecular event in watermelon domestication associated with a selection sweep around the ClTST2 promoter. Further molecular analyses explored the binding of a sugar-induced transcription factor (SUSIWM1) to a sugar-responsive cis-element within the ClTST2 promoter, which contains the quantitative trait locus (QTL) causal SNP. The functional characterization of ClTST2 and its expression regulation by SUSIWM1 provide novel tools to increase sugar sink potency in watermelon and possibly in other vegetable and fruit crops.

Method for accurate fiber length determination from increment cores for large-scale population analyses in Norway spruce

Abstract Fiber (tracheid) length is an important trait targeted for genetic and silvicultural improvement. Such studies require large-scale non-destructive sampling, and accurate length determination. The standard procedure for non-destructive sampling is to collect increment cores, singularize their cells by maceration, measure them with optical analyzer and apply various corrections to suppress influence of non-fiber particles and cut fibers, as fibers are cut by the corer. The recently developed expectation-maximization method (EM) not only addresses the problem of non-fibers and cut fibers, but also corrects for the sampling bias. Here, the performance of the EM method has been evaluated by comparing it with length-weighing and squared length-weighing, both implemented in fiber analyzers, and with microscopy data for intact fibers, corrected for sampling bias, as the reference. This was done for 12-mm increment cores from 16 Norway spruce (Picea abies (L.) Karst) trees on fibers from rings 8–11 (counted from pith), representing juvenile wood of interest in breeding programs. The EM-estimates provided mean-fiber-lengths with bias of only +2.7% and low scatter. Length-weighing and length2-weighing gave biases of -7.3% and +9.3%, respectively, and larger scatter. The suggested EM approach constitutes a more accurate non-destructive method for fiber length (FL) determination, expected to be applicable also to other conifers.

Association between mRNA expression of chemotherapy-related genes and clinicopathological features in colorectal cancer: A large-scale population analysis.

To establish the individualized treatment of patients with colorectal cancer, factors associated with chemotherapeutic effects should be identified. However, to the best of our knowledge, few studies are available on this topic, although it is known that the prognosis of patients and sensitivity to chemotherapy depend on the location of the tumor and that the tumor location is important for individualized treatment. In this study, primary tumors obtained from 1,129 patients with colorectal cancer were used to measure the mRNA expression levels of the following genes associated with the effects of standard chemotherapy for colorectal cancer: 5-fluorouracil (5-FU)-related thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP); folate-related dihydrofolate reductase (DHFR), folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH); irinotecan-related topoisomerase I (TOP1); oxaliplatin-related excision repair cross-complementing 1 (ERCC1); biologic agent-related vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Large-scale population analysis was performed to determine the association of gene expression with the clinicopathological features, in particular, the location of the colorectal cancer. From the results of our analysis of the mRNA expression of these 10 genes, we noted the strongest correlation between DPYD and TYMP, followed by TYMS and DHFR. The location of the colorectal cancer was classified into 4 regions (the right- and left-sided colon, rectosigmoid and rectum) and was compared with gene expression. A significant difference in all genes, apart from VEGF, was noted. Of the remaining 9 genes, the highest expression of TYMS and DPYD was observed in the right-sided colon; the highest expression of GGH and EGFR was noted in the left-sided colon; the highest expression of DHFR, FPGS, TOP1 and ERCC1 was noted in the rectosigmoid, whereas TYMP expression was approximately equivalent in the right-sided colon and rectum, and higher than that in other locations. The data generated from this study may prove to be useful for the development of individualized chemotherapeutic treatments for patients with colorectal cancer, and will mean that the tumor location is taken into account.

MALDI-TOF Mass Spectrometry for Multilocus Sequence Typing of Escherichia coli Reveals Diversity among Isolates Carrying blaCMY₋₂-Like Genes.

Effective surveillance and management of pathogenic Escherichia coli relies on robust and reproducible typing methods such as multilocus sequence typing (MLST). Typing of E. coli by MLST enables tracking of pathogenic clones that are known to carry virulence factors or spread resistance, such as the globally-prevalent ST131 lineage. Standard MLST for E. coli requires sequencing of seven alleles, or a whole genome, and can take several days. Here, we have developed and validated a nucleic-acid-based MALDI-TOF mass spectrometry (MS) method for MLST as a rapid alternative to sequencing that requires minimal operator expertise. Identification of alleles was 99.6% concordant with sequencing. We employed MLST by MALDI-TOF MS to investigate diversity among 62 E. coli isolates from Sydney, Australia, carrying a bla CMY-2-like gene on an IncI1 plasmid to determine whether any dominant clonal lineages are associated with the spread of this globally-disseminated resistance gene. Thirty-four known sequence types were identified, including lineages associated with human disease, animal and environmental sources. This suggests that the dissemination of bla CMY-2-like-genes is more complex than the simple spread of successful pathogenic clones. E. coli MLST by MALDI-TOF MS, employed here for the first time, can be utilised as an automated tool for large-scale population analyses or for targeted screening for known high-risk clones in a diagnostic setting.

Serum Albumin Levels: A Simple Answer to a Complex Problem? Are We on the Right Track of Assessing Metabolic Syndrome?

Serum Albumin Levels: A Simple Answer to a Complex Problem? Are We on the Right Track of Assessing Metabolic Syndrome?

PCR multiplex tool with 10 microsatellites for the European seabass ( Dicentrarchus labrax) — Applications in genetic differentiation of populations and parental assignment

The European seabass ( Dicentrarchus labrax) is a fish of high commercial value both from fisheries and aquaculture, especially in the Mediterranean countries. Population genetic studies with molecular markers have aimed at assessing the structure of wild and hatchery stocks, as well as evaluating genetic interactions between them. The increasing demand for population genetic studies in D. labrax prompts for robust and low cost genetic tagging tools for large-scale population analysis, to assist in genetic management and selection programs. The aim of this study was to develop a multiplex PCR technique adapted to automated DNA detection systems, taking advantage of the existing microsatellites from D. labrax. A 10 loci multiplex ( Dl10plex) with high allelic variability, high PIC value and no evidence of null alleles was obtained. Dl10plex was successfully applied to differentiating one Atlantic and one Mediterranean wild samples, as well as to effectively trace parents in an artificial cross, in which a large variation in parental contribution was detected. These results support its use in a standardized way, thus opening the possibility for a more reliable comparison of data from different sources and accelerating the understanding of D. labrax stock status, both in wild and cultivated populations.

Identification of gene signatures involved in the mechanisms of multidrug resistance.

Identification of gene signatures involved in the mechanisms of multidrug resistance.

Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expression levels in solid tumors in large scale population analysis

It has been reported that the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil (5-FU)-based therapy in cancer patients. We investigated the differences in the mRNA and protein expression of these enzymes in various tumor tissues. A total of 17,613 specimens of head and neck, gastric, colorectal, breast, lung and pancreatic cancer were collected from multiple facilities in Japan, and the mRNA and protein expression levels of the above enzymes were examined in 4,830 and 12,783 of these specimens, respectively. The mRNA levels were analyzed using RT-PCR in laser-captured microdissected formalin-fixed paraffin-embedded specimens, while the protein levels were analyzed by enzyme-linked immunosorbent assays. The median values of the relative TS, DPD and OPRT mRNA levels were 2.06, 0.803 and 1.17, respectively, while the median protein levels were 22.1, 134.8 and 3.81 ng enzyme/mg protein, respectively. The carcinomas were classified into two sets of four groups each using the overall median levels of TS and DPD or TS and OPRT as cutoff values. Approximately 60% of the gastric cancers exhibited elevated mRNA and protein expression levels of DPD, while >65% of the colorectal cancers showed low levels of DPD expression. Overall, 75% of the head and neck cancers exhibited high expression levels of DPD. Among the lung and pancreatic cancers, 50-74% showed low TS/high DPD expression. In conclusion, the mRNA expression and protein levels of TS, DPD and OPRT differed according to the type of cancer. The results of this large-scale population analysis are expected to be useful as reference data for predicting the relationship between the respective enzyme levels and the efficacy of 5-FU-based chemotherapy.