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PubMed1997

Sources of variation in biomarkers.

Epidemiology is interested in variation. The goal of epidemiological research is to infer cause-effect relationships by observing whether the occurrence of disease varies according to relevant exposures. Epidemiology is usually interested in 'intergroup' variation (e.g. between those who are exposed and those who are unexposed to the factor of interest), while 'intragroup' variation is a source of noise. Therefore, the study design aims to increase intergroup variability, to limit intragroup variability and to reduce error by ensuring validity and reliability of measurements. The goal of this chapter is to summarize simple ways to recognize the main sources of measurement error and to estimate the extent and the impact of such error.

Bias↗
PubMed1998

Evolution of a D2 dopamine receptor intron within the great apes and humans.

Although direct DNA sequencing may allow rapid and high quality comparative phylogenetic analyses among species, such an approach may not be the most efficient method by which to make a large number of cross-species comparisons. We illustrate the use of Denaturing Gradient Gel Electrophoresis (DGGE) to screen a D2 Dopamine Receptor intron for DNA sequence variation, both within and between closely related species, in order to infer their evolutionary relationships. Our results suggest that: a) humans have less genetic variation than the great apes; b) pygmy chimpanzees have less genetic variation than common chimpanzees; and c) DNA sequence comparative analyses of primates require adequate sampling, both in number and in geographical range.

Animals↗
PubMed2002

Moderators of placebo response to antipsychotic treatment in patients with schizophrenia: a meta-regression.

RATIONALE: Variation in placebo response within and among clinical trials involving patients with schizophrenia can substantially affect conclusions about the efficacy of new antipsychotic medications. Therefore, it is of great importance to identify factors that moderate response to placebo in such trials. OBJECTIVE: The objective of this meta-regression analysis was to estimate the effect of potential moderators of placebo response in randomized, short-term clinical trials involving patients with schizophrenia, schizoaffective disorder or schizophreniform disorder. METHODS: Mean placebo response and potential moderators were extracted from 35 placebo-controlled, randomized trials of antipsychotic medications in patients with schizophrenia. Placebo response was defined as the absolute change in the Brief Psychiatric Rating Scale total score. Fixed-effects meta-regression was used to investigate between-trial variation in placebo response. RESULTS: Trial duration accounted for a substantial proportion of the between-trial variation in response (27%), with greater improvement on placebo observed in shorter trials. Other variables showed insufficient variation across trials to permit any inferences regarding their relationships with placebo response. CONCLUSIONS: Placebo-controlled trials of short duration (<6-8 weeks) are vulnerable to substantial placebo response. Recruiting patients with more severe pathology to mitigate placebo response does not appear to offer benefits and may even be counterproductive. Meta-analyses based on individual patient data offer the potential for much more detailed and inferentially sound exploration of factors affecting placebo response and are highly recommended.

Adult↗
PubMed1991

Insulin dependent diabetes mellitus: an etiologic model.

The etiology of Insulin Dependent Diabetes Mellitus (IDDM) is reviewed and discussed using Rothman's deterministic model for causal inference. Intercontinental comparisons, familial aggregation, seasonal variation, maternal age, breast-feeding and infectious agents are reviewed within the context of IDDM causation. Genetic, viral and other environmental factors play a major role in this etiologic model.

Breast Feeding↗
PubMed2005

The generalizability of observational data to elderly patients was dependent on the research question in a systematic review.

BACKGROUND AND OBJECTIVE: Despite the increasing use of data derived from randomized controlled trials (RCTs) to perform observational studies, little is known about the validity of this approach. We compared inferences from studies that were performed using Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) RCT data with those derived from studies using data from the population-based Cooperative Cardiovascular Project (CCP). METHODS: We performed a systematic review. Articles were included if similar study questions were addressed by at least one manuscript that used GUSTO data and one that used CCP data. RESULTS: GUSTO findings were disparate from CCP data regarding absolute rates of specific process or outcome measures, such as thrombolysis-associated intracranial hemorrhage (ICH) (0.65% versus 1.43%, respectively), atrial fibrillation (10% versus 21%, respectively), or use of beta-blockers (58% versus 37%, respectively). However, many important relations noted in GUSTO were corroborated by studies using CCP data. Both data sets identified similar predictors of ICH and presentation delay. The degree of variability in beta-blocker use (across geographic region) and angiography use (between genders) was remarkably similar when studied using CCP or GUSTO data. CONCLUSION: Inferences derived from GUSTO about treatment variations and risk factors for outcomes were generalizable to community patients.

Aged↗
PubMed2005

Gold nanoparticle networks with photoresponsive interparticle spacings.

Photoresponsive gold nanoparticle networks were prepared by functionalizing them with azobenzene derivatives. A network can be formed when a linker molecule constituting the azobenzene moiety suitably derivatized on either side with gold surface sensitive groups such as thiols and amines is added to the nanoparticle solution. It is shown that the interparticle spacing in the networks could be controlled by the reversible trans-cis isomerization of the azobenzene moiety induced by UV and visible light, respectively. The photoinduced variation in the interparticle spacings is inferred by the changes in the optical spectra of the gold nanoparticles which display a red or blue shift in the surface plasmon resonance peak depending on a decrease or increase in the interparticle spacing, respectively. Transmission electron microscopy images are in consonance with the evidence from the optical spectra.

Azo Compounds↗
PubMed1999

Variation in the salivary peptide, maxadilan, from species in the Lutzomyia longipalpis complex.

Maxadilan is an approximately 7kDa peptide that occurs in the saliva of the sand fly Lutzomyia longipalpis. This peptide is a potent vasodilator and may also have immunomodulatory effects related to the pathogenesis of leishmanial infections. Variation in the primary DNA and inferred amino acid sequence of maxadilan is reported. Differences were found within and among natural field populations as well as among sibling species. Extensive amino acid sequence differentiation, up to 23%, was observed among maxadilan from different populations. This is a remarkable degree of polymorphism considering the small size of this peptide. The vasodilatory activity of maxadilan was equivalent among recombinant maxadilan variants. All maxadilan variants induce interleukin-6. Predicted secondary structure and hydrophobicity plots suggest that these characteristics are conserved among variant peptides. However, profiles based on the antigenic index do differ among peptides.

Animals↗
PubMed2004

Evolution of a RNA polymerase gene family in Silene (Caryophyllaceae)-incomplete concerted evolution and topological congruence among paralogues.

Four low-copy nuclear DNA intron regions from the second largest subunits of the RNA polymerase gene family (RPA2, RPB2, RPD2a, and RPD2b), the internal transcribed spacers (ITSs) from the nuclear ribosomal regions, and the rps16 intron from the chloroplast were sequenced and used in a phylogenetic analysis of 29 species from the tribe Sileneae (Caryophyllaceae). We used a low stringency nested polymerase chain reaction (PCR) approach to overcome the difficulties of constructing specific primers for amplification of the low copy nuclear DNA regions. Maximum parsimony analyses resulted in largely congruent phylogenetic trees for all regions. We tested overall model congruence in a likelihood context using the software PLATO and found that ITSs, RPA2, and RPB2 deviated from the maximum likelihood model for the combined data. The topology parameter was then isolated and topological congruence assessed by nonparametric bootstrapping. No strong topological incongruence was found. The analysis of the combined data sets resolves previously poorly known major relationships within Sileneae. Two paralogues of RPD2 were found, and several independent losses and incomplete concerted evolution were inferred. The among-site rate variation was significantly lower in the RNA polymerase introns than in the rps16 intron and ITSs, a property that is attractive in phylogenetic analyses.

DNA-Directed RNA Polymerases↗
PubMed2005

Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants.

A positional cloning study of type 2 diabetes in Mexican Americans identified a region, termed "NIDDM1," on chromosome 2q37 with significant linkage evidence. Haplotype combinations at the calpain-10 gene (CAPN10) within this region were shown to increase diabetes risk in several populations. On the basis of the thrifty genotype hypothesis, variants that increase susceptibility to type 2 diabetes under modern lifestyle conditions provided a survival advantage in past environments by increasing the efficiency of energy use and storage. Here, our goal is to make inferences about the evolutionary forces shaping variation in genes in the NIDDM1 region and to investigate the population genetics models that may underlie the thrifty genotype hypothesis. To this end, we surveyed sequence variation in CAPN10 and in an adjacent gene, G-protein-coupled receptor 35 (GPR35), in four population samples from different ethnic groups. These data revealed two distinct deviations from the standard neutral model in CAPN10, whereas GPR35 variation was largely consistent with neutrality. CAPN10 showed a significant deficit of variation in the haplotype class defined by the derived allele at SNP44, a polymorphism that is significantly associated with diabetes in meta-analysis studies. This suggests that this haplotype class was quickly driven to high frequency by positive natural selection. Interestingly, the derived allele at SNP44 is protective against diabetes. CAPN10 also showed a local excess of polymorphism and linkage disequilibrium decay in intron 13. Simulations show that this pattern may be explained by long-standing balancing selection that maintains multiple selected alleles. Alternatively, it is possible that the local mutation and recombination rates changed since the divergence of human and chimpanzee; this scenario does not require the action of natural selection on intron 13 variation.

Calpain↗
PubMed2002

Molecular identification of cyanobacteria associated with stromatolites from distinct geographical locations.

Modern stromatolites represent a significant resource for studying microbial ecology and evolution. A preliminary investigation was undertaken employing specific genetic probes to characterize the cyanobacteria responsible for stromatolite construction in a range of environments, including microbial mats found in Australia not previously examined with molecular methods. Isolates of cyanobacteria were collected from stromatolites in thermal springs, hypersaline lakes, and oceanic fringes on two continents. A polymerase chain reaction specific for DNA of cyanobacterial 16S rRNA was developed, the resulting products of the DNA amplification reaction were sequenced, and the data were used to infer relatedness between the isolates studied and other members of the cyanobacterial radiation. Complete sequence was generated for the region from position 27 to 408 for 13 strains of cyanobacteria associated with stromatolites. All stromatolite-derived sequences were most closely related to cyanobacteria, as indicated by local sequence alignment. It was possible to correlate genetic identity with morphological nomenclatures and to expand the phylogeny of benthic cyanobacteria. These inferences were also expanded to temporal variation in the dominant resident cyanobacterial species based on sampling of surface and core sinter laminations. Under the methods employed, only one cyanobacterial strain was detected in each sample, suggesting the possible dominance of a specific clonal population of cyanobacteria at any one time in the biota of the samples tested. The data indicate that internal core samples of a stromatolite at least 10 years old can be successfully analyzed by DNA-based methods to identify preserved cyanobacteria.

Base Sequence↗
PubMed1996

Human immunodeficiency virus type 1 molecular evolution and the measure of selection.

Human immunodeficiency virus (HIV) envelope genes are highly variable between and often within individuals. Part of this variability is thought to be the result of immune-mediated positive selection for sequence diversity. To measure positive selection it has become customary in HIV research to calculate the ratio of the proportions of synonymous (ds) and nonsynonymous (dn) substitutions per potential synonymous or nonsynonymous site, respectively. However, another measure that can be used is the difference between ds and dn, delta d. We show, by example, that using the ratio, ds/dn, or the difference, delta d, may lead us to different conclusions regarding the existence of positive selection pressure. We conclude by noting that until we understand the processes that mediate nucleotide variation in a host selective environment, inferences based on summary statistics characterizing types of nucleotide substitutions should be made with caution.

Base Sequence↗
PubMed2005

Phylogeographic inferences concerning evolution of Brazilian Passiflora actinia and P. elegans (Passifloraceae) based on ITS (nrDNA) variation.

BACKGROUND AND AIMS: Passiflora actinia and P. elegans, two markedly parapatric species, have their southern and northern distribution limits, respectively, in the most southern part of the Brazilian Atlantic Rain Forest. Despite the fact that they are classified in different taxonomic series, previous phylogenetic studies of this genus revealed a high genetic similarity between them. The aim of the present work was to analyse in more detail their geographical range in this region of overlap, to investigate intraspecific genetic variability and phylogeographic structure, and to search for possible hybrids. METHODS: Eighty-two localities were searched for these species, and nuclear internal transcribed spacer (ITS) sequences were investigated for 32 individuals of P. actinia, 20 of P. elegans and one putative interspecific hybrid. Plastid trnL-trnF and psbA-trnH were examined for 12 plants of each species and the putative hybrid. KEY RESULTS: Both species showed a high level of intraspecific and intra-individual ITS variability. Network analysis revealed a north-south geographic gradient in their intra and interspecific relationships. Mismatch analyses suggested a recent population expansion of P. elegans. The plastid markers showed restricted variability but, together with the nuclear data, they contributed to the identification of an interspecific hybrid of intermediate morphology at the border of the distribution of these two species. Both genetic and morphological data indicate the absence of an extensive hybridization zone between these species. CONCLUSIONS: Gene flow between lineages is the possible cause for the presence of different ITS sequences within a given plant, the absence of homogenization being due to the high degree of vegetative reproduction in the two species. Differentiation of P. actinia into geographic groups and the origin of P. elegans may have been influenced by the Atlantic Forest migration towards southern Brazil. The genetic pattern of the interspecific hybrid indicates that plastid inheritance in these species is at least sometimes paternal.

Base Sequence↗
PubMed2026

BaGGLS: a Bayesian shrinkage framework for interpretable modeling of interactions in high-dimensional biological data.

MOTIVATION: Biological data is often high dimensional, noisy, and governed by complex interactions among sparse signals. This poses major challenges for interpretability and reliable feature selection. Tasks such as identifying motif interactions in genomics exemplify these difficulties, as only a small subset of biologically relevant features (e.g. motifs) are typically active, and their effects are often non-linear and context-dependent. While statistical approaches often result in more interpretable models, deep learning models have proven effective in modeling complex interactions and prediction accuracy, yet their black-box nature limits interpretability. RESULTS: We introduce BaGGLS, a flexible and interpretable probabilistic binary regression model designed for high-dimensional biological inference involving feature interactions. BaGGLS incorporates a Bayesian group global-local shrinkage prior, aligned with the group structure introduced by interaction terms. This prior encourages sparsity while retaining interpretability, helping to isolate meaningful signals and suppress noise. To enable scalable inference, we employ a partially factorized variational approximation that captures posterior skewness and supports efficient learning even in large feature spaces. In extensive simulations, we compare BaGGLS to frequentist probit regressions (unconstrained and with L1-penalty) as well as a probit model with Markov Chain Monte Carlo (MCMC) sampling under a horseshoe prior. We can show that BaGGLS outperforms the other methods with regard to interaction detection and is many times faster than MCMC sampling under the horseshoe prior. We also demonstrate the usefulness of BaGGLS in the context of interaction discovery from motif scanner outputs (e.g. Find Individual Motif Occurrences (FIMO)) and noisy attribution scores from deep learning models. This shows that BaGGLS is a promising approach for uncovering biologically relevant interaction patterns, with potential applicability across a range of high-dimensional tasks in computational biology. AVAILABILITY: Code is available at gitlab.com/dacs-hpi/baggls.

Bayes Theorem↗
PubMedDate not supplied

Heritability of phenolics in Quercus laevis inferred using molecular markers.

Studies of quantitative inheritance of phenotypes do not generally encompass the range of environmental conditions to which a population may be exposed in a natural setting and are rarely conducted on long-lived species due to the time required for traditional crossing experiments. We used a marker-based method to estimate relatedness with microsatellite markers in a natural population of a long-lived oak, then used this inferred relatedness to examine quantitative genetic variation in the concentration of foliar phenolics. Estimating heritability using this method requires both significant relatedness and variance in relatedness over distance. However, this population did not show significant variance of relatedness, so only the presence of heritability, and its ranking among traits and environments, could be estimated. Seven foliar phenolics showed a significant relationship between phenotypic similarity and relatedness. The significance of this relationship varied among individual phenolic compounds, as well as by season. Genetic factors appeared to have a more measurable influence on the production of secondary compounds early in the season. After leaf expansion, covariance of relatedness and phenotypic variance appear to become less significant. Therefore heritability may vary seasonally for these traits.

Genetic Heterogeneity↗
PubMed2006

A Bayesian compound stochastic process for modeling nonstationary and nonhomogeneous sequence evolution.

Variations of nucleotidic composition affect phylogenetic inference conducted under stationary models of evolution. In particular, they may cause unrelated taxa sharing similar base composition to be grouped together in the resulting phylogeny. To address this problem, we developed a nonstationary and nonhomogeneous model accounting for compositional biases. Unlike previous nonstationary models, which are branchwise, that is, assume that base composition only changes at the nodes of the tree, in our model, the process of compositional drift is totally uncoupled from the speciation events. In addition, the total number of events of compositional drift distributed across the tree is directly inferred from the data. We implemented the method in a Bayesian framework, relying on Markov Chain Monte Carlo algorithms, and applied it to several nucleotidic data sets. In most cases, the stationarity assumption was rejected in favor of our nonstationary model. In addition, we show that our method is able to resolve a well-known artifact. By Bayes factor evaluation, we compared our model with 2 previously developed nonstationary models. We show that the coupling between speciations and compositional shifts inherent to branchwise models may lead to an overparameterization, resulting in a lesser fit. In some cases, this leads to incorrect conclusions, concerning the nature of the compositional biases. In contrast, our compound model more flexibly adapts its effective number of parameters to the data sets under investigation. Altogether, our results show that accounting for nonstationary sequence evolution may require more elaborate and more flexible models than those currently used.

Animals↗
PubMed1983

Species adaptation in a protein molecule.

The allosteric properties of hemoglobins, especially their responses to ligands other than oxygen, vary widely in different classes of vertebrates. Knowing the stereochemistry of the cooperative effects in human hemoglobin, one can infer the stereochemical basis of these variations from the changes in amino acid sequence. The results indicate that the tertiary and quaternary structures of deoxy- and oxyhemoglobin have remained almost invariant during vertebrate evolution and that most of the amino acid replacements between species are functionally neutral. Adaptations leading to responses to new chemical stimuli have evolved by only a few (one to five) amino acid substitutions in key positions. Once such a response has become superfluous, it may be inactivated, not necessarily by a reversal of one of the original substitutions but by any other that happens to inhibit it.

Adaptation, Physiological↗
PubMed1985

Modeling the electrophysiology of the corneal epithelium and its response to cellular injury.

A two-membrane equivalent electrical model was applied to the rabbit corneal epithelium. Single parameters were varied (with the other parameters kept constant) to generate equations predicting the electrical behavior of the corneal epithelium. Due to electrical feedback through the epithelial shunt, each transmembrane voltage is not solely a function of its own membrane parameters. The equations were evaluated with published data and the model successfully approximated the known electrical characteristics of the rabbit corneal epithelium. The principal site of voltage variation in the corneal epithelium is inferred from the slopes calculated from voltage scattergrams. Reduced shunt resistance results from injury to the corneal epithelium in vitro, or from hard contact lens wear in vivo.

Animals↗
PubMed2003

Refugial origins of reindeer (Rangifer tarandus L.) inferred from mitochondrial DNA sequences.

The glacial-interglacial cycles of the upper Pleistocene have had a major impact on the recent evolutionary history of Arctic species. To assess the effects of these large-scale climatic fluctuations to a large, migratory Arctic mammal, we assessed the phylogeography of reindeer (Rangifer tarandus) as inferred from mitochondrial DNA (mtDNA) sequence variation in the control region. Phylogenetic relationships among haplotypes seem to reflect historical patterns of fragmentation and colonization rather than clear-cut relationships among extant populations and subspecies. Three major haplogroups were detected, presumably representing three separate populations during the last glacial. The most influential one has contributed to the gene pool of all extant subspecies and seems to represent a large and continuous glacial population extending from Beringia and far into Eurasia. A smaller, more localized refugium was most likely isolated in connection with ice expansion in western Eurasia. A third glacial refugium was presumably located south of the ice sheet in North America, possibly comprising several separate refugial populations. Significant demographic population expansion was detected for the two haplogroups representing the western Eurasian and Beringian glacial populations. The former apparently expanded when the ice cap retreated by the end of the last glacial. The large continuous one, in contrast, seems to have expanded by the end of the last interglacial, indicating that the warm interglacial climate accompanied by marine transgression and forest expansion significantly confined population size on the continental mainland. Our data demonstrate that the current subspecies designation does not reflect the mtDNA phylogeography of the species, which in turn may indicate that morphological differences among subspecies have evolved as adaptive responses to postglacial environmental change.

Animals↗