MotivationThe identification of biomarkers to support decision-making is central to personalized medicine, in both clinical and research scenarios. The challenge can be seen in two halves: identifying predictive markers, which guide the development/use of tailored therapies; and identifying prognostic markers, which guide other aspects of care and clinical trial planning, i.e. prognostic markers can be considered as covariates for stratification. Mistakenly assuming a biomarker to be predictive, when it is in fact largely prognostic (and vice-versa) is highly undesirable, and can result in financial, ethical and personal consequences. We present a framework for data-driven ranking of biomarkers on their prognostic/predictive strength, using a novel information theoretic method. This approach provides a natural algebra to discuss and quantify the individual predictive and prognostic strength, in a self-consistent mathematical framework.ResultsOur contribution is a novel procedure, INFO+, which naturally distinguishes the prognostic versus predictive role of each biomarker and handles higher order interactions. In a comprehensive empirical evaluation INFO+ outperforms more complex methods, most notably when noise factors dominate, and biomarkers are likely to be falsely identified as predictive, when in fact they are just strongly prognostic. Furthermore, we show that our methods can be 1–3 orders of magnitude faster than competitors, making it useful for biomarker discovery in ‘big data’ scenarios. Finally, we apply our methods to identify predictive biomarkers on two real clinical trials, and introduce a new graphical representation that provides greater insight into the prognostic and predictive strength of each biomarker.Availability and implementationR implementations of the suggested methods are available at https://github.com/sechidis.Supplementary information Supplementary data are available at Bioinformatics online.

We conclude that IGP measurement during test-meal infusion represents an efficient and novel method to compare gastric accommodation and peristaltic motility in the whole stomach of conscious rats.

The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin (ob/ob) double-null mice (MCHr1 knockout ob/ob) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight. Diabetes 55:725-733, 2006 I t is well known that obesity is a major contributing factor to the development of insulin resistance and type 2 diabetes. Diabetic patients can often reverse their insulin resistance by decreasing their body weight. However, the mechanism linking obesity and insulin sensitivity is poorly understood. Mutations in the ob gene results in obesity and insulin resistance, and this may serve as a model for increased food intake leading to obesity and insulin resistance.Melanin-concentrating hormone (MCH) was originally isolated and sequenced from salmon pituitary and was named MCH due to its role in fish pigmentation (1). In rodents, MCH is predominantly expressed in the lateral hypothalamus and zona incerta, areas involved in the regulation of energy homeostasis and ingestive behavior. MCH fibers project broadly throughout the central nervous system, suggesting that MCH may function as a neurotransmittor and/or a neuromodulator to regulate behavioral functions (2,3). There is much data to support a role for MCH in the regulation of food intake, body weight, and energy balance. This includes the expression profile of MCH in the lateral hypothalamus and the fact that both fasting and leptin deficiency result in elevated MCH levels (4). Overexpression of MCH in transgenic mice given high-fat diet results in weight gain, hyperphagia, obesity, and insulin resistance (5). Chronic infusion of MCH results in hyperphagia and obesity in mice (6). Mice deficient of MCH are hypophagic, lean, and have an increased metabolic rate (7). Also, treatment of rats with an MCH receptor antagonist results in inhibition of food intake and weight loss (8). Furthermore, the central role of MCH and the MCH receptor-1 (MCHr1) for energy balance is supported by the phenotypes of MCHr1 knockout mice (9 -11). One important difference between the MCH knockout and MCHr1 knockout mice is that the latter are slightly hyperphagic but still lean due to increased energy expenditure. The rodent receptor for MCH, MCHr1 (or SL...

One of the most widely used animal models for inflammatory bowel disease (IBD) is the dextran sulfate sodium (DSS)‐induced colitis. We have previously reported that 5 days administration of DSS in C57Bl/6J mice induces a colonic inflammation that progresses into chronicity after DSS removal, whereas in BALB/cJ mice the inflammation resolves within 4 weeks post‐DSS. Here we show that both thymic size and thymocyte numbers dramatically decreased in the acute phase of inflammation in C57Bl/6 mice, 7 days after DSS withdrawal. Mature, CD4+ and CD8+ single positive (SP) CD69lo CD62Lhi thymocytes were enriched in these mice, accompanied by a major decrease in the number of immature double positive (DP) thymocytes. However, the different maturation stages within the DP thymocyte subset were unchanged between healthy and inflamed C57Bl/6J mice. Interestingly, as the inflammation progressed into the chronic phase, the thymus recovered and 2 weeks after the acute inflammatory phase all the thymic parameters investigated in this study were restored to normal. In contrast, BALB/cJ mice only develop mild thymic alterations. Nevertheless, we found that within the double negative (DN) thymocytes an increased frequency and also total numbers of CD44+ CD25− (DN1) cells correlated with the severety of colitis, and that the frequency of CD44− CD25− (DN4) thymocytes decreased proportionally in the acute phase in BALB/cJ mice. Our observations suggest that the thymic effects are intimately connected to the intestinal inflammatory response in colitis regardless of the inflammatory stimuli.

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