Exploring the Hidden Complexity: Entropy Analysis in Pulse Oximetry of Female Athletes.

This study examines the relationship between physiological complexity, as measured by Approximate Entropy (ApEn) and Sample Entropy (SampEn), and fitness levels in female athletes. Our focus is on their association with maximal oxygen consumption (VO2,max). Our findings reveal a complex relationship between entropy metrics and fitness levels, indicating that higher fitness typically, though not invariably, correlates with greater entropy in physiological time series data; however, this is not consistent for all individuals. For Heart Rate (HR), entropy measures suggest stable patterns across fitness categories, while pulse oximetry (SpO2) data shows greater variability. For instance, the medium fitness group displayed an ApEn(HR) = 0.57±0.13 with a coefficient of variation (CV) of 22.17 and ApEn(SpO2) = 0.96±0.49 with a CV of 46.08%, compared to the excellent fitness group with ApEn(HR) = 0.60±0.09 with a CV of 15.19% and ApEn(SpO2) =0.85±0.42 with a CV of 49.46%, suggesting broader physiological responses among more fit individuals. The larger standard deviations and CVs for SpO2 entropy may indicate the body's proficient oxygen utilization at higher levels of physical demand. Our findings advocate for combining entropy metrics with wearable sensor technology for improved biomedical analysis and personalized healthcare.

Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.

Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers.

A strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10-5) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate -0.006 kg/m2, 95% CI -0.009 to -0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.

Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country.

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.

Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape.

We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value <5 × 10-8) at 42 genome regions, nine of which have been previously reported. In follow-up analyses, 26 of the 33 novel regions replicate in East Asians, Europeans, or Africans, and one mouse homologous region influences craniofacial morphology in mice. The novel region in 1q32.3 shows introgression from Neanderthals and we find that the introgressed tract increases nasal height (consistent with the differentiation between Neanderthals and modern humans). Novel regions include candidate genes and genome regulatory elements previously implicated in craniofacial development, and show preferential transcription in cranial neural crest cells. The automated approach used here should simplify the collection of large study samples from across the world, facilitating a cosmopolitan characterization of the genetics of facial features.

Dental size variation in admixed Latin Americans: Effects of age, sex and genomic ancestry.

Dental size variation in modern humans has been assessed from regional to worldwide scales, especially under microevolutionary and forensic contexts. Despite this, populations of mixed continental ancestry such as contemporary Latin Americans remain unexplored. In the present study we investigated a large Latin American sample from Colombia (N = 804) and obtained buccolingual and mesiodistal diameters and three indices for maxillary and mandibular teeth (except third molars). We evaluated the correlation between 28 dental measurements (and three indices) with age, sex and genomic ancestry (estimated using genome-wide SNP data). In addition, we explored correlation patterns between dental measurements and the biological affinities, based on these measurements, between two Latin American samples (Colombians and Mexicans) and three putative parental populations: Central and South Native Americans, western Europeans and western Africans through PCA and DFA. Our results indicate that Latin Americans have high dental size diversity, overlapping the variation exhibited by the parental populations. Several dental dimensions and indices have significant correlations with sex and age. Western Europeans presented closer biological affinities with Colombians, and the European genomic ancestry exhibited the highest correlations with tooth size. Correlations between tooth measurements reveal distinct dental modules, as well as a higher integration of postcanine dentition. The effects on dental size of age, sex and genomic ancestry is of relevance for forensic, biohistorical and microevolutionary studies in Latin Americans.

Skin Pigmentation Influence on Pulse Oximetry Accuracy: A Systematic Review and Bibliometric Analysis.

Nowadays, pulse oximetry has become the standard in primary and intensive care units, especially as a triage tool during the current COVID-19 pandemic. Hence, a deeper understanding of the measurement errors that can affect precise readings is a key element in clinical decision-making. Several factors may influence the accuracy of pulse oximetry, such as skin color, body temperature, altitude, or patient movement. The skin pigmentation effect on pulse oximetry accuracy has long been studied reporting some contradictory conclusions. Recent studies have shown a positive bias in oxygen saturation measurements in patients with darkly pigmented skin, particularly under low saturation conditions. This review aims to study the literature that assesses the influence of skin pigmentation on the accuracy of these devices. We employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to conduct a systematic review retrospectively since February 2022 using WOS, PubMed, and Scopus databases. We found 99 unique references, of which only 41 satisfied the established inclusion criteria. A bibliometric and scientometrics approach was performed to examine the outcomes of an exhaustive survey of the thematic content and trending topics.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression.

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence "gallstones → dysplasia → GBC". In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04-1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.

Inbreeding, Native American ancestry and child mortality: linking human selection and paediatric medicine.

The children of related parents show increased risk of early mortality. The Native American genome typically exhibits long stretches of homozygosity, and Latin Americans are highly heterogeneous regarding the individual burden of homozygosity, the proportion and the type of Native American ancestry. We analysed nationwide mortality and genome-wide genotype data from admixed Chileans to investigate the relationship between common causes of child mortality, homozygosity and Native American ancestry. Results from two-stage linear-Poisson regression revealed a strong association between the sum length of runs of homozygosity (SROH) above 1.5 Megabases (Mb) in each genome and mortality due to intracranial non-traumatic haemorrhage of foetus and newborn (5% increased risk of death per Mb in SROH, P = 1 × 10-3) and disorders related to short gestation and low birth weight (P = 3 × 10-4). The major indigenous populations in Chile are Aymara-Quechua in the north of the country and the Mapuche-Huilliche in the south. The individual proportion of Aymara-Quechua ancestry was associated with an increased risk of death due to anencephaly and similar malformations (P = 4 × 10-5), and the risk of death due to Edwards and Patau trisomy syndromes decreased 4% per 1% Aymara-Quechua ancestry proportion (P = 4 × 10-4) and 5% per 1% Mapuche-Huilliche ancestry proportion (P = 2 × 10-3). The present results suggest that short gestation, low birth weight and intracranial non-traumatic haemorrhage mediate the negative effect of inbreeding on human selection. Independent validation of the identified associations between common causes of child death, homozygosity and fine-scale ancestry proportions may inform paediatric medicine.

Prediction of eye, hair and skin colour in Latin Americans.

Here we evaluate the accuracy of prediction for eye, hair and skin pigmentation in a dataset of > 6500 individuals from Mexico, Colombia, Peru, Chile and Brazil (including genome-wide SNP data and quantitative/categorical pigmentation phenotypes - the CANDELA dataset CAN). We evaluated accuracy in relation to different analytical methods and various phenotypic predictors. As expected from statistical principles, we observe that quantitative traits are more sensitive to changes in the prediction models than categorical traits. We find that Random Forest or Linear Regression are generally the best performing methods. We also compare the prediction accuracy of SNP sets defined in the CAN dataset (including 56, 101 and 120 SNPs for eye, hair and skin colour prediction, respectively) to the well-established HIrisPlex-S SNP set (including 6, 22 and 36 SNPs for eye, hair and skin colour prediction respectively). When training prediction models on the CAN data, we observe remarkably similar performances for HIrisPlex-S and the larger CAN SNP sets for the prediction of hair (categorical) and eye (both categorical and quantitative), while the CAN sets outperform HIrisPlex-S for quantitative, but not for categorical skin pigmentation prediction. The performance of HIrisPlex-S, when models are trained in a world-wide sample (although consisting of 80% Europeans, https://hirisplex.erasmusmc.nl), is lower relative to training in the CAN data (particularly for hair and skin colour). Altogether, our observations are consistent with common variation of eye and hair colour having a relatively simple genetic architecture, which is well captured by HIrisPlex-S, even in admixed Latin Americans (with partial European ancestry). By contrast, since skin pigmentation is a more polygenic trait, accuracy is more sensitive to prediction SNP set size, although here this effect was only apparent for a quantitative measure of skin pigmentation. Our results support the use of HIrisPlex-S in the prediction of categorical pigmentation traits for forensic purposes in Latin America, while illustrating the impact of training datasets on its accuracy.

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans.

BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.

A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia.

We report a genome-wide association scan in >6,000 Latin Americans for pigmentation of skin and eyes. We found eighteen signals of association at twelve genomic regions. These include one novel locus for skin pigmentation (in 10q26) and three novel loci for eye pigmentation (in 1q32, 20q13 and 22q12). We demonstrate the presence of multiple independent signals of association in the 11q14 and 15q13 regions (comprising the GRM5/TYR and HERC2/OCA2 genes, respectively) and several epistatic interactions among independently associated alleles. Strongest association with skin pigmentation at 19p13 was observed for an Y182H missense variant (common only in East Asians and Native Americans) in MFSD12, a gene recently associated with skin pigmentation in Africans. We show that the frequency of the derived allele at Y182H is significantly correlated with lower solar radiation intensity in East Asia and infer that MFSD12 was under selection in East Asians, probably after their split from Europeans.

A geometric morphometric approach to the study of variation of shovel-shaped incisors.

OBJECTIVES: The scoring and analysis of dental nonmetric traits are predominantly accomplished by using the Arizona State University Dental Anthropology System (ASUDAS), a standard protocol based on strict definitions and three-dimensional dental plaques. However, visual scoring, even when controlled by strict definitions of features, visual reference, and the experience of the observer, includes an unavoidable part of subjectivity. In this methodological contribution, we propose a new quantitative geometric morphometric approach to quickly and efficiently assess the variation of shoveling in modern human maxillary central incisors (UI1). MATERIALS AND METHODS: We analyzed 87 modern human UI1s by means of virtual imaging and the ASU-UI1 dental plaque grades using geometric morphometrics by placing semilandmarks on the labial crown aspect. The modern human sample was composed of individuals from Europe, Africa, and Asia and included representatives of all seven grades defined by the ASUDAS method. RESULTS: Our results highlighted some limitations in the use of the current UI1 ASUDAS plaque, indicating that it did not necessarily represent an objective gradient of expression of a nonmetric tooth feature. Rating of shoveling tended to be more prone to intra- and interobserver bias for the highest grades. In addition, our analyses suggest that the observers were strongly influenced by the depth of the lingual crown aspect when assessing the shoveling. DISCUSSION: In this context, our results provide a reliable and reproducible framework reinforced by statistical results supporting the fact that open scale numerical measurements can complement the ASUDAS method.

Variation in dental morphology and inference of continental ancestry in admixed Latin Americans.

OBJECTIVES: To investigate the variation in dental nonmetric traits and to evaluate the utility of this variation for inferring genetic ancestry proportions in a sample of admixed Latin Americans. MATERIALS AND METHODS: We characterized a sample from Colombia (N = 477) for 34 dental traits and obtained estimates of individual Native American, European, and African ancestry using genome-wide SNP data. We tested for correlation between dental traits, genetic ancestry, age, and sex. We carried out a biodistance analysis between the Colombian sample and reference continental population samples using the mean measure of divergence statistic calculated from dental trait frequencies. We evaluated the inference of genetic ancestry from dental traits using a regression approach (with 10-fold cross-validation) as well as by testing the correlation between estimates of ancestry obtained from genetic and dental data. RESULTS: Latin Americans show intermediate dental trait frequencies when compared to Native Americans, Europeans, and Africans. Significant correlations were observed for several dental traits, genetic ancestry, age, and sex. The biodistance analysis displayed a closer relationship of Colombians to Europeans than to Native Americans and Africans. Mean ancestry estimates obtained from the dental data are similar to the genetic estimates (Native American: 32% vs. 28%, European: 59% vs. 63%, and African: 9% vs. 9%, respectively). However, dental features provided low predictive power for genetic ancestry of individuals in both approaches tested (R2 < 5% for all genetic ancestries across methods). DISCUSSION: The frequency of dental traits in Latin Americans reflects their admixed Native American, European and African ancestry and can provide reasonable average estimates of genetic ancestry. However, the accuracy of individual genetic ancestry estimates is relatively low, probably influenced by the continental differentiation of dental traits, their genetic architecture, and the distribution of genetic ancestry in the individuals examined.

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance.

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.