From Molecules to Patients: The Clinical Applications of Translational Bioinformatics.

OBJECTIVE: In order to realize the promise of personalized medicine, Translational Bioinformatics (TBI) research will need to continue to address implementation issues across the clinical spectrum. In this review, we aim to evaluate the expanding field of TBI towards clinical applications, and define common themes and current gaps in order to motivate future research. METHODS: Here we present the state-of-the-art of clinical implementation of TBI-based tools and resources. Our thematic analyses of a targeted literature search of recent TBI-related articles ranged across topics in genomics, data management, hypothesis generation, molecular epidemiology, diagnostics, therapeutics and personalized medicine. RESULTS: Open areas of clinically-relevant TBI research identified in this review include developing data standards and best practices, publicly available resources, integrative systemslevel approaches, user-friendly tools for clinical support, cloud computing solutions, emerging technologies and means to address pressing legal, ethical and social issues. CONCLUSIONS: There is a need for further research bridging the gap from foundational TBI-based theories and methodologies to clinical implementation. We have organized the topic themes presented in this review into four conceptual foci - domain analyses, knowledge engineering, computational architectures and computation methods alongside three stages of knowledge development in order to orient future TBI efforts to accelerate the goals of personalized medicine.

Relationship between tissue mobilization and storage in the rat.

The amount of energy mobilized or stored as protein, expressed as a proportion of the total energy stored or mobilized (defined as the P ratio, Payne & Dugdale, 1977), was investigated in the young male (rapid growth) and adult female (slow growth) rat. Energy mobilization was induced by a 3 d fast and the changes in body content of fat and lean tissues were used to estimate the fasting P ratio (Pfast). Tissue storage was subsequently effected by 17 d of refeeding and the corresponding ratio (P(refed)) was calculated from the amounts of lean and fat tissue regained. The same experimental protocol was used for measuring Pfast and P(refed) in weanling (30 d) and adult (130 d) rats. Weight-matched individuals were assigned to three groups. All animals in group 1 were killed at the beginning of the experiment. Animals in group 2 were fasted for 3 d and then killed. Group 3 animals were first fasted for 3 d, then had free access to a stock diet for a further 17 d before being killed. During fasting, a close linear relationship was found between weight change and body energy changes (r 0.985, and r 0.92, P < 0.001 for weanlings and adult rats respectively) and between carcass N loss and urinary N loss (r 0.933, P < 0.001). These relationships were used to estimate the body energy and N content of each animal at the end of the initial fasting period. Hence, both Pfast and P(refed) values could be calculated for all individuals at both ages. When Pfast and P(refed) were calculated for adult rats, the mean values were similar (0.138 (SE 0.002) and 0.130 (SE 0.006) respectively). Individually, the Pfast and P(refed) values were correlated (r 0.54, P = 0.058). In weanling rats, the mean P(refed) value was about 2.5 times the Pfast (0.421 (SE 0.0113) v. 0.156 (SE 0.004)). Despite the differences in Pfast and p(refed), the individual values were again correlated (r 0.668, P < 0.05). These results support the suggestion made by Payne & Dugdale (1977), that particular P. ratio values are characteristic of individuals and describe the extent to which protein is mobilized or stored during fasting or refeeding. These observations are discussed in relations to the predictions made by the Payne-Dugdale model.

Protein utilization, growth and survival in essential-fatty-acid-deficient rats.

The relationship between essential fatty acids (EFA) deficiency and the utilization of dietary protein, growth rate and survival of offspring was investigated in rats during development and reproduction. EFA deficiency was induced by feeding a 200 g casein/kg-based diet containing 70 g hydrogenated coconut oil (HCO)/kg as the only source of fat. The conversion efficiency of dietary protein was assessed as net protein utilization (NPU), using a 10 d comparative carcass technique. Consumption of the deficient diet during the 10 d assay period induced biochemical changes characteristic of mild EFA deficiency in humans (triene:tetraene 0.27 (SD 0.04) compared with 0.026 (SD 0.004) for non-deficient controls), but there were no significant changes in growth rate or protein utilization. These variables were also unchanged when the deficient diet was fed for an additional 7 d before the assay, although triene:tetraene increased to 0.8 (SD 0.02). Feeding the deficient diet for 63 d before assay produced severe EFA deficiency (triene:tetraene 1.4 (SD 0.3) v. 0.036 (SD 0.005) for controls), a fall in growth rate (25% during assay period), and NPU (31.5 (SD 0.63) v. 39.0 (SD 0.93) for controls). These severely-EFA-deficient animals had a 30% higher fasting-resting rate of energy metabolism than that of age-matched controls. However, there was no change in the rate of endogenous N loss. Voluntary energy consumption was increased in animals fed on deficient diets, either with 200 g protein/kg, or protein free. The reduced efficiency of protein utilization could be entirely accounted for by the restricted amount of energy available for growth and protein deposition. Consumption of an EFA-deficient diet during pregnancy and lactation resulted in high mortality (11% survival rate at weaning compared with 79% for controls) and retarded growth in the preweaning offspring. It is concluded that animals are particularly sensitive to EFA deficiency during reproduction and pre- and post-natal stages of development. However, after weaning only severe EFA deficiency retarded growth, primarily through changes in energy balance.

Metabolic rate and physical development in children at risk of obesity.

Children of obese (group O) and normal-weight (group N) parents who took part in a study of metabolic rates and food intakes when 3-5 years old were restudied 12 years later. There were striking differences between the sexes. Among the 15 adolescent boys, parental obesity predicted more rapid growth (but not adiposity) and an earlier decline in resting metabolic rate (RMR)/kg body weight, and childhood energy intake/kg body weight was not predictive. Among the 10 girls, the opposite pattern was observed; childhood energy intake/kg predicted both body size and adiposity, and parental obesity had less predictive value. The sex differences are consistent with the earlier maturation of girls, and the growth differences with the hypothesis that a low RMR/kg body weight is associated with a precocious pattern of growth and development in children predisposed to obesity.

Protein and energy metabolism in starvation reconsidered.

Current concepts of the metabolic changes during starvation have been heavily influenced by recent studies on grossly obese subjects undergoing therapeutic fasting. It has been suggested that during prolonged starvation the central nervous system develops the ability to utilize ketone bodies, and that the consequent reduction in gluconeogenesis leads to an adaptive sparing of protein catabolism. However, our analysis of classical studies on starvation shows that during prolonged starvation in normal subjects the fraction of total energy expenditure derived from protein (the P ratio) remained unchanged. Although urinary nitrogen was reduced during the progress of the fast, we conclude that this is secondary to the general reduction in metabolic rate, rather than to a specific sparing of protein.

Energy intake in children at high and low risk of obesity.

This study compared 7-d energy intakes of 37 young children at low (Group N) and high (Group O) risk of subsequent obesity, as judged from parental obesity. The energy intake of Group O was 16 per cent lower than Group N (P = 0.02). Although the intakes of all the children considered together and also Group N children alone showed the usual wide variability and absence of correlation with body size, the intakes of Group O children were significantly correlated with their weight and height (r = 0.5). The results confirm a previous study and suggest that, since basal metabolic rate and body weight are known to be correlated, attention should be focused on differences in expenditure in investigations of the aetiology of childhood obesity.

Basal metabolic rate of Indian men: no evidence of metabolic adaptation to a low plane of nutrition.

Basal metabolic rate (BMR) was measured in 58 men of a rural Indian population who had low body weight and body fat stores. Comparisons of subgroups of subjects of different socio-economic status and different nutritional status showed no evidence of differences in BMR when corrected for differences in body weight and body fat content. This suggests that metabolic adaptation did not account for differences in absolute BMR between subgroups of this population. The BMR values agreed well with values predicted by equations based on BMR measurements in Asian men of higher body weight, but were below values predicted by the new FAO/WHO/UNU prediction equations by an average of 12.1 per cent (P less than 0.0001). This overprediction could be a reflection of allometric or climatic influences on BMR rather than evidence for metabolic adaptation to a low plane of energy nutrition.

Urethrocliesis--a simple cure for stress incontinence.

Urethrocliesis is a vaginal operation for stress incontinence in which the whole length of the urethra is narrowed by two rows of non-absorbable sutures. A 2-year follow-up of the first 62 patients shows that 60 patients were satisfied with the results of their operation: a result that compares favourably with any of the other surgical procedures used for stress incontinence. The simplicity of the operation, and the fact that it can be applied to the old and young with an equal degree of success, commends it as an initial line of treatment in the management of stress incontinence.

Nutritional status indicators: interpretation and policy making role.

PIP: Anthropometric measurements, usually based on the growth of children, and considered to be reflective of the degree and state of nutritional status, have long been the measurement of choice in assessing the health and welfare of a community. However, it must be borne in mind that any such measure serves only as an indicator of the functioning of a very complex system. As such it is subject to error when applied according to rigid and predetermined numeral scales reflecting social valuations, and really cannot be considered to be a technical description of a physiological state. The limitations to the application of such inferred nutritional data, from a systems viewpoint, are many and should be recognized. Nonetheless, measures of nutritional status can provide valuable information on the effects of the health, social and food environment of individuals and communities. Bearing in mind the limitations of their usefulness, such measurements can serve as useful tools in policy making and can be integrated with information from other sectors of government for this purpose.^ieng

A comparison of different methods of instrumental delivery based on electronic measurements of compression and traction.

Electronic measurements of compression, using a hydrostatic technique, were made during 44 normal deliveries and compared with the values obtained during 32 deliveries using Kielland's forceps, 21 using Neville Barnes' forceps, 48 using Moolgaoker's adjustable forceps, and 26 using Malmstrom's vacuum extractor. Electronic recordings of traction, using strain gauges, were made simultaneously during all the instrumental deliveries except those with Kielland's forceps. By exercising suitable controls over most of the multiple factors operating at the time of any delivery the authors were able to compare objectively the efficiency of the different methods of instrumental delivery. Smaller forces of compression and traction were exerted and better Apgar scores were recorded in infants delivered with the adjustable forceps than in infants delivered with the other instruments. The superiority of the adjustable forceps was most noticeable during midcavity deliveries of the malrotated head.

Functional classification of undernourished populations in the Republic of El Salvador. Methodological development.

Typical government nutrition programmes usually lack precise information on the size of groups that could benefit from interventions, on the different types of potential beneficiaries and their location, and on socio-economic and cultural characteristics through which they could readily be identified. In the functional classification approach to the definition of nutritional problems, detailed information on human behaviour and social constraints is collected at family and community levels. The data are then interpreted in general terms in order to understand how these factors contribute to inadequate levels of nutrition within larger groups. This new approach should enable more effective measures for reducing the numbers of those living under conditions of deprivation to be presented to planners and decision makers.

Method to quantify ride comfort and allowable accelerations.

When the motion of a vehicle includes "shocks" or impulsive velocity changes, R.M.S. acceleration has no relation to crew comfort or injury. Existing (R.M.S. G) methods of ride assessment can show lethal accelerations as being perfectly safe, and vice versa. It follows that R.M.S. acceleration is not meaningful for nonsinusoidal "random" vibration either. This paper presents a method of evading the difficulty, using fairly well established biodynamic modeling techniques, and an extension of Allen's "shock tolerance" concept. Among other advantages, the method "automates" the assessment of ride quality so that personal judgments are not involved and the relative ride quality of different vehicles can be placed on a quantitative basis. Since this work was inspired by the problem of Navy crew tolerance to the motions of high-speed ships, the discussion is in those terms. Also, the proposed criteria should probably be scaled down for more general populations.

A model for the prediction of energy balance and body weight.

A model for changes in energy balance and body weight is described which can be written as an iterative computer program. Medium and long-term changes in body weight resulting from random daily fluctuations in energy balance are quantitatively predicted. Body weight varies periodically about a mean value to to the extent of +/- 1 kg over a span of a few weeks. Long-term weight stabilization is the result of a dynamic equilibrium between energy intake and output which depends on activity and tissue metabolism. A lean : fat tissue deposition ratio defines the metabolic type of individual. This ration, which is constant for each individual, governs the proportions in which these tissues are both deposited and mobilized. In the model, the ratio has an important effect on the magnitude and composition of the weight gains resulting from over-eating. It is suggested that the differences in response which have been observed in over-eating experiments result from inter-individual differences in this ratio.

Reducing the hospital stay following vaginal hysterectomy.

A rapidly increasing waiting list in a new National Health service district general hospital made it necessary to explore measures to reduce the length of hospital stay of gynecologic inpatients without lowering the standards of medical care. Three years of experience with patients undergoing vaginal hysterectomy after January 1972 is described. During this time, 290 vaginal hysterectomies were performed and combined with pelvic floor repair in 194 cases. The average hospital stay for such patients was 12.7 days in 1971 before this study was commenced; since then this has been reduced progressively to 7.2 days with a corresponding increase in the number of such operations carried out annually. The effects of routine chemoprophylaxis and a modified technic of vault closure are discussed.