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Integrating gene and protein expression data: pattern analysis and profile mining.

Proteomics and functional genomics are emerging new research fields devoted to the study of the entire collection of proteins and mRNA transcripts (collectively known as gene products) that define a biological system. DNA microarrays are now a popular platform for measuring changes in messenger RNA transcript levels on a genome-wide scale, while gel-free shotgun profiling methods based on tandem mass spectrometry are increasingly being used to determine the identity, modification states, and relative abundance of large numbers of proteins. By defining the behavior of entire biological pathways and networks under various physiological states, these studies aim to extend traditional reductionist molecular genetic approaches regarding the biological roles of the vast array of uncharacterized gene products. A key goal is to determine how the information encoded by the myriad of expressed gene products is integrated at the molecular, cellular, and even whole organism level to create the dynamic biochemical processes and complex physiological controls that sustain life. While comparison of the complementary information contained in proteomic and mRNA data sets poses considerable analytical challenges, these efforts should provide added insight into the fundamental mechanisms underlying physiology, development, and the emergence of disease. Here, we outline several analytical approaches, methods, and tools that have proven to be helpful in the face of this important challenge.

Algorithms↗

The integration of measurement and management for the treatment of bipolar disorder: a STEP-BD model of collaborative care in psychiatry.

Patients with bipolar disorder are among the most challenging to treat. These patients frequently present with complex mood and other symptoms that change over time, complex psychiatric and medical comorbid conditions, and multiple medications. Clinicians rarely systematically assess or measure all of these factors and instead rely on memory and general impressions. It is imperative that clinicians systematically track and monitor these relevant variables to ensure treatment decisions are based on precise clinical data. By integrating measurement and management, clinicians and patients can collaborate to assess the effectiveness of treatments and to make joint decisions about critical points at which to adjust treatment. This method was shown to be successful in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

Bipolar Disorder↗

Reducing the incidence of falls in high risk patients.

The incidence of patient falls in any acute and chronic care facility is a continuing challenge for nursing administrators. A computerized program was designed to identify common characteristics of 180 patients who had experienced a fall during 1986 at a midwest hospital. Based on analysis of the data, an integrated process of assessment, diagnosis, and intervention was developed and implemented. Early indications of success have been identified.

Accident Prevention↗

Rat 22kHz ultrasonic vocalizations as alarm cries.

Rats incorporate circa 22kHz ultrasonic alarm cries into their defense pattern in response to a predator threat. These calls are dependent on conspecific presence, show gender differences, and tend to be emitted from a place of relative safety. Rats emit sonic defensive threat vocalizations when approached by a potential threat. These are emitted regardless of conspecific presence, and increase as a function of threat proximity, eventually culminating in defensive attack at close distances. Ample data from field studies suggest a similar division of vocalizations into alarm or warning cries, and defensive threat vocalizations, although both are often subsumed under the rubric of "alarm cries". A clear distinction between these types of calls is necessary for proper analysis of the evolutionary mechanisms responsible for the development and maintenance of each of them. Furthermore, the integration of data from field studies and laboratory experiments may prove useful in evaluation of the relationship between each type of cry and emotional (fear or anxiety-like) states in mammals.

Animals↗

Genomic Features Do Not Account for Differences in Multiple Myeloma Risk by Ancestry.

UNLABELLED: Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. SIGNIFICANCE: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

Humans↗

An information-driven approach to pharmacogenomics.

Effective information management of the pharmacogenomics discipline presents many unique challenges. Genetic and genomic data generated via high-throughput methods need to be integrated with phenotypic data which are defined at multiscale levels, ranging from the molecular to the clinical level. Repositories storing these data are distributed and vary in terms of syntax and semantics which result in issues concerning data exchange and integration. The application of the emerging semantic web offers a promising solution to these interoperability issues.

Animals↗

Normative data on low back mobility and activity levels. Implications for neuromuscular reeducation.

Low back mobility and electromyographic movements were performed in 121 normal subjects, grouped by age and sex. Women tended to show greater ranges of motion for straight leg raising, trunk rotation and lateral bending while vertebral separation (forward flexion) was greater in men. A sex-age interaction was observed only in lateral bending, thus implying that for other mobility measurements, data within the age groupings employed in this study can be combined for men and women. Electromyographic data were integrated and quantified using EMG biofeedback equipment for unilateral or bilateral recordings made primarily from the erector spinae muscle between lumbar 3-4 and lumbar 4-5 levels, three centimeters lateral to the spinous processes. Dynamic (trunk flexion-extension, lateral rotation-standing, stooping) and static (quiet sitting, rotation-sitting) movements were performed over a ten second interval. Data analyses verified previous electromyographic studies by demonstrating the trunk extensor function of the erector spinae and the relatively greater unilateral activity when turning to the opposite direction in the erect posture. EMG silence was seen during full trunk flexion. Noticeable sex-age interaction were observed for all dynamic movements but not for static activities. Therefore, it is suggested that EMG data during dynamic movements in a normal population cannot be grouped for men and women within a specified age distribution. These data represent one series of baselines to which mobility and movement patterns in a back pain patient group can be compared. Suggestions are offered for the use of EMG biofeedback during dynamic lower back movements as a possible method of alleviating the pain state, perhaps by altering the patient's posture.

Adolescent↗

Black light: how sensors filter spectral variation of the illuminant.

Visual sensor responses may be used to classify objects on the basis of their surface reflectance functions. In a color image, the image data are represented as a vector of sensor responses at each point in the image. This vector depends both on the surface reflectance function and on the spectral power distribution of the ambient illumination. Algorithms designed to classify objects on the basis of their surface reflectance functions typically attempt to overcome the dependence of the sensor responses on the illuminant by integrating sensor data collected from multiple surfaces. In machine vision applications, we show that it is often possible to design the sensor spectral responsivities so that the vector direction of the sensor responses does not depend upon the illuminant. We state the conditions under which this is possible and perform an illustrative calculation. In biological systems, where the sensor responsivities are fixed, we show that some changes in the illumination cause no change in the sensor responses. We call such changes in illuminant black illuminants. It is possible to express any illuminant as the sum of two unique components. One component is a black illuminant. We call the second component the visible component. The visible component of an illuminant completely characterizes the effect of the illuminant on the vector of sensor responses.

Artificial Intelligence↗

Socioeconomic inequality of cancer mortality in the United States: a spatial data mining approach.

BACKGROUND: The objective of this study was to demonstrate the use of an association rule mining approach to discover associations between selected socioeconomic variables and the four most leading causes of cancer mortality in the United States. An association rule mining algorithm was applied to extract associations between the 1988-1992 cancer mortality rates for colorectal, lung, breast, and prostate cancers defined at the Health Service Area level and selected socioeconomic variables from the 1990 United States census. Geographic information system technology was used to integrate these data which were defined at different spatial resolutions, and to visualize and analyze the results from the association rule mining process. RESULTS: Health Service Areas with high rates of low education, high unemployment, and low paying jobs were found to associate with higher rates of cancer mortality. CONCLUSION: Association rule mining with geographic information technology helps reveal the spatial patterns of socioeconomic inequality in cancer mortality in the United States and identify regions that need further attention.

Algorithms↗

Empirical data and moral theory. A plea for integrated empirical ethics.

Ethicists differ considerably in their reasons for using empirical data. This paper presents a brief overview of four traditional approaches to the use of empirical data: "the prescriptive applied ethicists," "the theorists," "the critical applied ethicists," and "the particularists." The main aim of this paper is to introduce a fifth approach of more recent date (i.e. "integrated empirical ethics") and to offer some methodological directives for research in integrated empirical ethics. All five approaches are presented in a table for heuristic purposes. The table consists of eight columns: "view on distinction descriptive-prescriptive sciences," "location of moral authority," "central goal(s)," "types of normativity," "use of empirical data," "method," "interaction empirical data and moral theory," and "cooperation with descriptive sciences." Ethicists can use the table in order to identify their own approach. Reflection on these issues prior to starting research in empirical ethics should lead to harmonization of the different scientific disciplines and effective planning of the final research design. Integrated empirical ethics (IEE) refers to studies in which ethicists and descriptive scientists cooperate together continuously and intensively. Both disciplines try to integrate moral theory and empirical data in order to reach a normative conclusion with respect to a specific social practice. IEE is not wholly prescriptive or wholly descriptive since IEE assumes an interdepence between facts and values and between the empirical and the normative. The paper ends with three suggestions for consideration on some of the future challenges of integrated empirical ethics.

Empirical Research↗

Probing Electrostatic Forces in Colloidal Suspensions through Turbidity Data.

This paper deals with the use of turbidimetry to obtain information on forces between negatively charged polymeric particles at very low ionic strength. The specific turbidity of deionized colloidal suspensions is measured and compared with the values obtained for suspensions of noninteracting particles. From these data, the integrated structure factors are experimentally obtained for several latex samples. These functions are fitted using the repulsive part of the DLVO potential, the Ornstein-Zernike equation, and the hyper-netted chain closure, which enables us to interpret the results in terms of an effective charge. The reliability of these values is discussed. In addition, a comparison between turbidimetry and light scattering data is presented. Copyright 1999 Academic Press.

Journal Article↗

ECHO: a nanopore sequencing-based workflow for (epi)genetic profiling of the human repeatome.

SUMMARY: The human genome is dominated by repetitive DNA, whose genetic and epigenetic variation plays a key role in gene regulation, genome stability, and disease. Recent advances in long-read sequencing now enable large-scale, haplotype-resolved, and DNA methylation-informative analysis of the human genome, including on previously inaccessible complex and repetitive regions. However, the comprehensive, simultaneous characterisation of the "human repeatome" remains challenging, largely due to the lack of comprehensive tools integrated in a single pipeline that can capture the full spectrum of variation across diverse types of DNA repeats. Here, we present ECHO, a user-friendly, Snakemake-based pipeline for the "(Epi)genomic Characterisation of Human Repetitive Elements using Oxford Nanopore Sequencing." ECHO provides a reproducible and scalable framework for end-to-end analysis of whole-genome nanopore sequencing data, enabling integrative but also tailored (epi)genetic analyses of the human repeatome. AVAILABILITY AND IMPLEMENTATION: ECHO is freely available at Github: https://github.com/leenput/ECHO-pipeline, with the archived version at Zenodo: https://zenodo.org/records/19068468.

Humans↗

Quantitative trait loci mapping of gene expression and chromatin accessibility in primary fibroblasts reveals shared allelic effects between Latin American and European ancestries.

BACKGROUND: Quantitative Trait Locus (QTL) analysis of molecular data has identified genetic variants associated with traits such as gene expression, and colocalization of these functional QTL with GWAS risk loci has offered insights into the genetic basis of human disease. We employed gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) obtained from human primary fibroblasts to investigate quantitative trait loci (QTLs) in cohorts ascertained for bipolar disorder of European (n = 150) and Latin American (n = 96) ancestries. RESULTS: Leveraging data from three countries of origin (The Netherlands, Colombia, Costa Rica) within our cohort, we characterized differences among individuals at the SNP, gene, and accessible-chromatin levels to compute ancestry-specific expression (e)QTLs and chromatin-accessibility (ca)QTLs. Across ancestries, we observed R2 ≥ 0.93 for eQTL effect sizes and R2 ≥ 0.95 for caQTLs, indicating a high degree of concordance. Integrating chromatin data with expression and genotype information enabled precise fine-mapping of eQTLs, yielding 203 genes with high-confidence (posterior probability > 90%) candidate regulatory pathways. In downstream analyses, transcriptome-wide (TWAS) and chromatin-wide (CWAS) association studies with brain- and skin-related GWAS identified 36 TWAS-significant genes and 77 CWAS-significant open chromatin regions. CONCLUSIONS: These findings underscore the shared genetic regulatory mechanisms across European and Latin American ancestries, while demonstrating that ancestry-specific reference panels enhance the accuracy of TWAS and CWAS in diverse populations. More broadly, this study highlights the value of paired multi-omic datasets from diverse cohorts for interpreting disease-associated genetic variation.

Humans↗

[Behavior of plasma pancreatic polypeptides and motilin in obese patients subjected to biliopancreatic bypass].

Biliopancreatic bypass for obesity entails a 2/3 distal gastrectomy with Roux-en-y reconstruction, being the small bowel transected at its midpoint and the enteroenteroanastomosis placed 50 cm proximal to the ileocecal value. Pancreatic polypeptide (PP) and motilin fasting and meal-stimulated plasma concentrations were determined in 13 nonobese healthy volunteers, in 13 nonoperated obese patients, in 9 subjects within two months, in 12 subjects four to twelve months, and in 7 subjects fifteen to twenty months after operation. There were no significant differences in PP fasting levels between either the obese and control groups or between the postoperative groups and the preoperative group. Both meal-stimulated peak and integrated response values were similar in the obese and control groups, and were strikingly and progressively reduced postoperatively, with statistically significant difference between all postoperative groups and preoperative group. Mean plasma motilin fasting and peak values were higher in the obese group than in the control group, and significantly reduced in the 4-12 and 15-20 month group. Despite the huge variability among data, the integrated response in the 0-2 month group was significantly decreased in comparison with the preoperative group, while a subsequent progressive increase was shown by the 4-12 and 15-20 month groups.

Fasting↗

A regression-based method for mapping traffic-related air pollution: application and testing in four contrasting urban environments.

Accurate, high-resolution maps of traffic-related air pollution are needed both as a basis for assessing exposures as part of epidemiological studies, and to inform urban air-quality policy and traffic management. This paper assesses the use of a GIS-based, regression mapping technique to model spatial patterns of traffic-related air pollution. The model--developed using data from 80 passive sampler sites in Huddersfield, as part of the SAVIAH (Small Area Variations in Air Quality and Health) project--uses data on traffic flows and land cover in the 300-m buffer zone around each site, and altitude of the site, as predictors of NO2 concentrations. It was tested here by application in four urban areas in the UK: Huddersfield (for the year following that used for initial model development), Sheffield, Northampton, and part of London. In each case, a GIS was built in ArcInfo, integrating relevant data on road traffic, urban land use and topography. Monitoring of NO2 was undertaken using replicate passive samplers (in London, data were obtained from surveys carried out as part of the London network). In Huddersfield, Sheffield and Northampton, the model was first calibrated by comparing modelled results with monitored NO2 concentrations at 10 randomly selected sites; the calibrated model was then validated against data from a further 10-28 sites. In London, where data for only 11 sites were available, validation was not undertaken. Results showed that the model performed well in all cases. After local calibration, the model gave estimates of mean annual NO2 concentrations within a factor of 1.5 of the actual mean (approx. 70-90%) of the time and within a factor of 2 between 70 and 100% of the time. r2 values between modelled and observed concentrations are in the range of 0.58-0.76. These results are comparable to those achieved by more sophisticated dispersion models. The model also has several advantages over dispersion modelling. It is able, for example, to provide high-resolution maps across a whole urban area without the need to interpolate between receptor points. It also offers substantially reduced costs and processing times compared to formal dispersion modelling. It is concluded that the model might thus be used as a means of mapping long-term air pollution concentrations either in support of local authority air-quality management strategies, or in epidemiological studies.

Air Pollutants↗

Micro-Mar: a database for dynamic representation of marine microbial biodiversity.

BACKGROUND: The cataloging of marine prokaryotic DNA sequences is a fundamental aspect for bioprospecting and also for the development of evolutionary and speciation models. However, large amount of DNA sequences used to quantify prokaryotic biodiversity requires proper tools for storing, managing and analyzing these data for research purposes. DESCRIPTION: The Micro-Mar database has been created to collect DNA diversity information from marine prokaryotes for biogeographical and ecological analyses. The database currently includes 11874 sequences corresponding to high resolution taxonomic genes (16S rRNA, ITS and 23S rRNA) and many other genes including CDS of marine prokaryotes together with available biogeographical and ecological information. CONCLUSION: The database aims to integrate molecular data and taxonomic affiliation with biogeographical and ecological features that will allow to have a dynamic representation of the marine microbial diversity embedded in a user friendly web interface. It is available online at http://egg.umh.es/micromar/.

Base Sequence↗

Magnetic resonance imaging in right ventricular dysplasia.

Fifteen patients with right ventricular dysplasia were investigated by T1-weighted spin- and gradient-echo pulse sequences, using a protocol that enabled both a subjective analysis of myocardial signal intensity and a quantitative/qualitative analysis of right and left ventricular function. In 8 patients, 3 investigators independently recognized abnormally hyperintense areas in the anatomic sites usually affected by the disease. In 7 of these patients, these areas showed an overlap with a-dyskinetic areas imaged by both magnetic resonance imaging (MRI) and echocardiography. In 1 patient who underwent a cardiac transplant, MRI of the explanted heart showed an excellent correlation between the distribution of the lesions and the in vivo/in vitro features. The data were compared with those from an equivalent sample of patients affected by dilated cardiomyopathy. In the latter patients, no focal hyperintensities were attributed to any anatomic sites in the right ventricule, and no focal a-dyskinetic foci were observed. Furthermore, the 2 groups of patients were significantly different in regard to dimensional and functional quantitative parameters. The results suggest that MRI is useful in integrating echocardiographic data and can be helpful in diagnosing this disease in late stages.

Adipose Tissue↗

Flux and stability: individual fluctuations, regression towards the mean and collective changes in alcohol consumption.

AIM: First, to extend the predictions of the collectivity theory of drinking cultures to contexts of ordinary panel data, thereby integrating collective change and individual fluctuations in consumption. Secondly, to develop a technique for controlling the regression towards the mean effect, in order to estimate the pattern of individual change, net of this effect. DESIGN: The task is, first and foremost, to develop a theoretical model, guided by earlier contributions and empirical results. The applicability of the model is illustrated through re-analyses of panel data on annual intake of alcoholic beverages from the Finnish alcohol reform in 1968-69, and Norwegian panel data from 1975 to 1976. FINDINGS: The model offers a reasonable fit to the data. It is demonstrated that a previous attempt at controlling the regression effect has overlooked a methodological complication, and therefore underestimates the real change. CONCLUSION: Analysis of the Finnish data demonstrates that the large increase in average consumption was due to approximately the same percentage-wise increase in the consumption level of drinkers at all levels, when the regression effect was controlled for. Thus, in absolute terms the increase was largest among the heavier drinkers.

Alcohol Drinking↗

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