Sex-Specific Skeletal Muscle Gene Expression Responses to Exercise Reveal Novel Direct Mediators of Insulin Sensitivity Change.

BACKGROUND: Understanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise. METHODS: The study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount. RESULTS: In women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. CONCLUSIONS: The signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.

Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis.

OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1ß and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1ß, TNFα, VEGF, IL-6, IL-6Rα, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.

Trends and developments in bioinformatics in 2010: prospects and perspectives.

OBJECTIVES: To survey major developments and trends in the field of Bioinformatics in 2010 and their relationships to those of previous years, with emphasis on long-term trends, on best practices, on quality of the science of informatics, and on quality of science as a function of informatics. METHODS: A critical review of articles in the literature of Bioinformatics over the past year. RESULTS: Our main results suggest that Bioinformatics continues to be a major catalyst for progress in Biology and Translational Medicine, as a consequence of new assaying technologies, most pre-dominantly Next Generation Sequencing, which are changing the landscape of modern biological and medical research. These assays critically depend on bioinformatics and have led to quick growth of corresponding informatics methods development. Clinical-grade molecular signatures are proliferating at a rapid rate. However, a highly publicized incident at a prominent university showed that deficiencies in informatics methods can lead to catastrophic consequences for important scientific projects. Developing evidence-driven protocols and best practices is greatly needed given how serious are the implications for the quality of translational and basic science. CONCLUSIONS: Several exciting new methods have appeared over the past 18 months, that open new roads for progress in bioinformatics methods and their impact in biomedicine. At the same time, the range of open problems of great significance is extensive, ensuring the vitality of the field for many years to come.

Formative evaluation of a prototype system for automated analysis of mass spectrometry data.

Mass Spectrometry (MS) is emerging as a breakthrough mass-throughput technology capable of producing powerful clinical diagnostic and prognostic models and of identifying important disease biomarkers. Few individuals possess the necessary skills to carry out MS analyses competently, and access to such individuals is limited in most settings, hindering progress in this field. We seek to ease this burden by creating a fully automated system (FAST-AIMS) capable of analyzing mass spectra to produce high-quality diagnostic and outcome prediction models and identify related biomarkers. In the present report we introduce the system and conduct a formative evaluation in which 6 users apply it to a challenging dataset. FAST-AIMS' performance is compared to that of an expert statistician as well as to a previously published analysis by an independent group. In our experiments FAST-AIMS when used by both MS-sophisticated users (n=4) and naïve users (n=2) achieves performance (a) comparable to our human expert, and (b) superior to the previously published manual analysis; in addition (c) the system's estimates future performance accurately, thus avoiding overfitting.

HITON: a novel Markov Blanket algorithm for optimal variable selection.

UNLABELLED: We introduce a novel, sound, sample-efficient, and highly-scalable algorithm for variable selection for classification, regression and prediction called HITON. The algorithm works by inducing the Markov Blanket of the variable to be classified or predicted. A wide variety of biomedical tasks with different characteristics were used for an empirical evaluation. Namely, (i) bioactivity prediction for drug discovery, (ii) clinical diagnosis of arrhythmias, (iii) bibliographic text categorization, (iv) lung cancer diagnosis from gene expression array data, and (v) proteomics-based prostate cancer detection. State-of-the-art algorithms for each domain were selected for baseline comparison. RESULTS: (1) HITON reduces the number of variables in the prediction models by three orders of magnitude relative to the original variable set while improving or maintaining accuracy. (2) HITON outperforms the baseline algorithms by selecting more than two orders-of-magnitude smaller variable sets than the baselines, in the selected tasks and datasets.

Text categorization models for retrieval of high quality articles in internal medicine.

The discipline of Evidence Based Medicine (EBM) studies formal and quasi-formal methods for identifying high quality medical information and abstracting it in useful forms so that patients receive the best customized care possible [1]. Current computer-based methods for finding high quality information in PubMed and similar bibliographic resources utilize search tools that employ preconstructed Boolean queries. These clinical queries are derived from a combined application of (a) user interviews, (b) ad-hoc manual document quality review, and (c) search over a constrained space of disjunctive Boolean queries. The present research explores the use of powerful text categorization (machine learning) methods to identify content-specific and high-quality PubMed articles. Our results show that models built with the proposed approach outperform the Boolean based PubMed clinical query filters in discriminatory power.

Machine learning models for lung cancer classification using array comparative genomic hybridization.

Array CGH is a recently introduced technology that measures changes in the gene copy number of hundreds of genes in a single experiment. The primary goal of this study was to develop machine learning models that classify non-small Lung Cancers according to histopathology types and to compare several machine learning methods in this learning task. DNA from tumors of 37 patients (21 squamous carcinomas, and 16 adenocarcinomas) were extracted and hybridized onto a 452 BAC clone array. The following algorithms were used: KNN, Decision Tree Induction, Support Vector Machines and Feed-Forward Neural Networks. Performance was measured via leave-one-out classification accuracy. The best multi-gene model found had a leave-one-out accuracy of 89.2%. Decision Trees performed poorer than the other methods in this learning task and dataset. We conclude that gene copy numbers as measured by array CGH are, collectively, an excellent indicator of histological subtype. Several interesting research directions are discussed.

Issues and opportunities in public health informatics: a panel discussion.

A panel was convened at the American Medical Informatics Association Spring Congress to discuss issues and opportunities that arise when informatics methods, theories, and applications are applied to public health functions. Panelists provided examples of applications that connect efforts between public health and clinical care, emphasizing the need for integration of clinical data with public health data and the analysis of those data to support surveillance and informed decision making. Benefits to be gained by both medical informatics and public health at the interface were evident; both encounter the same major issues including privacy, systems integration, standards, and many more.

Temporal representation design principles: an assessment in the domain of liver transplantation.

Time modeling is an important aspect of medical decision-support systems engineering. At the core of effective time modeling lies the challenge of proper knowledge representation design. In this paper, we focus on two important principles for effective time-modeling languages: (a) hybrid temporal representation, and (b) dynamic temporal abstraction. To explore the significance of these design principles, we extend a previously-defined formalism (single-granularity modifiable temporal belief networks--MTBN-SGs) to accommodate multiple temporal granularities and dynamic query and domain-specific model creation. We call the new formalism multiple-granularity MTBNs (MTBN-MGs). We develop a prototype system for modeling aspects of liver transplantation and analyze the resulting model with respect to its representation power, representational tractability, and inferential tractability. Our experiment demonstrates that the design of formalisms is crucial for effective time modeling. In particular: (i) Hybrid temporal representation is a desirable property of time-modeling languages because it makes knowledge acquisition easier, and increases representational tractability. (ii) Dynamic temporal abstraction improves inferential and representational tractability significantly. We discuss a high-level procedure for extending existing languages to incorporate hybrid temporal representation and dynamic temporal abstraction.

Representing and developing temporally abstracted knowledge as a means towards facilitating time modeling in medical decision-support systems.

The utilization of the appropriate level of temporal abstraction is an important aspect of time modeling. We discuss some aspects of the relation of temporal abstraction to important knowledge engineering parameters such as model correctness, ease of model specification, knowledge availability, query completeness, inference tractability, and semantic clarity. We propose that versatile and efficient time-modeling formalisms should encompass ways to represent and reason at more than one level of abstraction, and we discuss such a hybrid formalism. Although many research efforts have concentrated on the automation of specific temporal abstractions, much research needs to be done in understanding and developing provably optimal abstractions. We provide an initial framework for studying this problem in a manner that is independent of the particular problem domain and knowledge representation, and suggest several research challenges that appear worth pursuing.

An evaluation of machine-learning methods for predicting pneumonia mortality.

This paper describes the application of eight statistical and machine-learning methods to derive computer models for predicting mortality of hospital patients with pneumonia from their findings at initial presentation. The eight models were each constructed based on 9847 patient cases and they were each evaluated on 4352 additional cases. The primary evaluation metric was the error in predicted survival as a function of the fraction of patients predicted to survive. This metric is useful in assessing a model's potential to assist a clinician in deciding whether to treat a given patient in the hospital or at home. We examined the error rates of the models when predicting that a given fraction of patients will survive. We examined survival fractions between 0.1 and 0.6. Over this range, each model's predictive error rate was within 1% of the error rate of every other model. When predicting that approximately 30% of the patients will survive, all the models have an error rate of less than 1.5%. The models are distinguished more by the number of variables and parameters that they contain than by their error rates; these differences suggest which models may be the most amenable to future implementation as paper-based guidelines.

A temporal analysis of QMR.

OBJECTIVE: To understand better the trade-offs of not incorporating explicit time in Quick Medical Reference (QMR), a diagnostic system in the domain of general internal medicine, along the dimensions of expressive power and diagnostic accuracy. DESIGN: The study was conducted in two phases. Phase I was a descriptive analysis of the temporal abstractions incorporated in QMR's terms. Phase II was a pseudo-prospective controlled experiment, measuring the effect of history and physical examination temporal content on the diagnostic accuracy of QMR. MEASUREMENTS: For each QMR finding that would fit our operational definition of temporal finding, several parameters describing the temporal nature of the finding were assessed, the most important ones being: temporal primitives, time units, temporal uncertainty, processes, and patterns. The history, physical examination, and initial laboratory results of 105 consecutive patients admitted to the Pittsburgh University Presbyterian Hospital were analyzed for temporal content and factors that could potentially influence diagnostic accuracy (these included: rareness of primary diagnosis, case length, uncertainty, spatial/causal information, and multiple diseases). RESULTS: 776 findings were identified as temporal. The authors developed an ontology describing the terms utilized by QMR developers to express temporal knowledge. The authors classified the temporal abstractions found in QMR in 116 temporal types, 11 temporal templates, and a temporal hierarchy. The odds of QMR's making a correct diagnosis in high temporal complexity cases is 0.7 the odds when the temporal complexity is lower, but this result is not statistically significant (95% confidence interval = 0.27-1.83). CONCLUSIONS: QMR contains extensive implicit time modeling. These results support the conclusion that the abstracted encoding of time in the medical knowledge of QMR does not induce a diagnostic performance penalty.

On the heuristic nature of medical decision-support systems.

In the realm of medical decision-support systems, the term "heuristic systems" is often considered to be synonymous with "medical artificial intelligence systems" or with "systems employing informal model(s) of problem solving". Such a view may be inaccurate and possibly impede the conceptual development of future systems. This article examines the nature of heuristics and the levels at which heuristic solutions are introduced during system design and implementation. The authors discuss why heuristics are ubiquitous in all medical decision-support systems operating at non-trivial domains, and propose a unifying definition of heuristics that encompasses formal and ad hoc systems. System developers should be aware of the heuristic nature of all problem solving done in complex real world domains, and characterize their own use of heuristics in describing system development and implementation.

A new formalism for temporal modeling in medical decision-support systems.

We present a new mathematical formalism, which we call modifiable temporal belief networks (MTBNs) that extends the concept of an ordinary belief network (BN) to incorporate a dynamic causal structure and explicit temporal semantics. An important feature of MTBNs is that they allow portions of the model to be abstract and portions of it to be temporally explicit. We show how this property can lead to substantial knowledge acquisition and computational complexity savings. In addition to temporal modeling, the language of MTBNs can be an important analytical tool, as well as temporal language for causal discovery.

Temporal reasoning abstractions in QMR.

A medical decision-support system (MDSS) employs either explicit or implicit temporal representation and reasoning (TRR). In this paper we first examine the factors that make explicit TRR necessary. We argue that for diagnostic MDSSs in large domains, such as internal medicine, implicit TRR is often sufficient for acceptable diagnostic performance. A necessary prerequisite for implementing implicit TRR is the identification of a set of proper TRR abstractions. We analyze the implicit TRR utilized in QMR, a MDSS operating in the domain of general internal medicine, and describe three classes of TRR abstractions. We discuss our findings in relation to work on temporal reasoning in medical informatics.

Incidence of gynaecomastia in 954 young males and its relationship to somatometric parameters.

The incidence of gynaecomastia was evaluated in 954 healthy young men aged 18-26 years, and was correlated with several somatometric parameters (height, weight, testes size, eye colour, scalp hair colour, scalp hair density, acne, density and extent of body hair). Gynaecomastia (> 2 cm breast tissue) was found in 40.5% (bilateral 85%, left 7.8%, right 7.2%) of the subjects. Highly statistically significant differences were found between subjects with or without gynaecomastia in their weight (79.7 +/- 10.7 kg versus 69.1 +/- 7.8 kg respectively; p < 0.001) and in their body hair (subjects with gynaecomastia had more dense and extensive body hair than those without; p < 0.001). When the density and extent of body hair was analysed separately for each age, it was found that subjects with gynaecomastia had completed the development of body hair earlier, since 80% of them had completed their body hair by the age of 23 years versus only 45% of those without gynaecomastia. This observation leads to the assumption that obesity and/or an earlier maturation of the subjects with gynaecomastia may play a role in the development of breast tissue, although the possibility of an increased tissue sensitivity to hormonal action cannot be excluded.

A temporal analysis of QMR: abstracted temporal representation and reasoning and initial assessment of diagnostic performance trade-offs.

Explicit temporal representation and reasoning (TRR) in medical decision-support systems (MDSS) is generally considered to be a useful but often neglected aspect of system design and implementation. Given the great burden of explicit TRR both in knowledge acquisition and computational efficiency, developers of general-purpose large-scale systems typically utilize implicit (i.e., abstracted) forms of TRR. We are interested in understanding better the trade-offs of not incorporating explicit TRR in large general-purpose MDSS along the dimensions of system expressive power and diagnostic accuracy. In particular, we examine the types of abstracted TRR employed in QMR, a diagnostic system in the domain of general internal medicine, and the high-level effects of such an implicit treatment of time in the system's diagnostic performance. We present our findings and discuss implications for MDSS design and implementation practices.