Classification of clinical outcomes using high-throughput and clinical informatics.

It is widely recognized that many cancer therapies are effective only for a subset of patients. However clinical studies are most often powered to detect an overall treatment effect. To address this issue, classification methods are increasingly being used to predict a subset of patients which respond differently to treatment. This study begins with a brief history of classification methods with an emphasis on applications involving melanoma. Nonparametric methods suitable for predicting subsets of patients responding differently to treatment are then reviewed. Each method has different ways of incorporating continuous, categorical, clinical and high-throughput covariates. For nonparametric and parametric methods, distance measures specific to the method are used to make classification decisions. Approaches are outlined which employ these distances to measure treatment interactions and predict patients more sensitive to treatment. Simulations are also carried out to examine empirical power of some of these classification methods in an adaptive signature design. Results were compared with logistic regression models. It was found that parametric and nonparametric methods performed reasonably well. Relative performance of the methods depends on the simulation scenario. Finally a method was developed to evaluate power and sample size needed for an adaptive signature design in order to predict the subset of patients sensitive to treatment. It is hoped that this study will stimulate more development of nonparametric and parametric methods to predict subsets of patients responding differently to treatment

The effect of caffeine on cognitive performance is influenced by CYP1A2 but not ADORA2A genotype, yet neither genotype affects exercise performance in healthy adults

Purpose: To determine the influence of two commonly occurring genetic polymorphisms on exercise, cognitive performance, and caffeine metabolism, after caffeine ingestion. Methods: Eighteen adults received caffeine or placebo (3 mg kg−1) in a randomised crossover study, with measures of endurance exercise (15-min cycling time trial; 70-min post-supplementation) and cognitive performance (psychomotor vigilance test; PVT; pre, 50 and 95-min post-supplementation). Serum caffeine and paraxanthine were measured (pre, 30 and 120-min post-supplementation), and polymorphisms in ADORA2A (rs5751876) and CYP1A2 (rs762551) genes analysed.Results: Caffeine enhanced exercise performance (P  0.05). Caffeine enhanced PVT performance (P  0.05). Serum caffeine and paraxanthine responses were not different between genotypes (P > 0.05).Conclusion: Caffeine enhanced CYP1A2 ‘fast’ metabolisers’ cognitive performance more than ‘slow’ metabolisers. No other between-genotype differences emerged for the effect of caffeine on exercise or cognitive performance, or metabolism

Vitamin D metabolites are associated with musculoskeletal injury in young adults: a prospective cohort study.

The relationship between vitamin D metabolites and lower body (pelvis and lower limb) overuse injury is unclear. In a prospective cohort study, we investigated the association between vitamin D metabolites and incidence of lower body overuse musculoskeletal and bone stress injury in young adults undergoing initial military training during all seasons. In 1637 men and 530 women (age, 22.6 ± 7.5 years; BMI, 24.0 ± 2.6 kg∙m−2; 94.3% white ethnicity), we measured serum 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) by high-performance liquid chromatography tandem mass spectrometry, and 1,25-dihydroxyvitamin D (1,25(OH)2D) by immunoassay during week 1 of training. We examined whether the relationship between 25(OH)D and 1,25(OH)2D:24,25(OH)2D ratio was associated with overuse injury. During 12 weeks training, 21.0% sustained ≥1 overuse musculoskeletal injury, and 5.6% sustained ≥1 bone stress injury. After controlling for sex, BMI, 2.4 km run time, smoking, bone injury history, and Army training course (Officer, standard, or Infantry), lower body overuse musculoskeletal injury incidence was higher for participants within the second lowest versus highest quartile of 24,25(OH)2D (OR: 1.62 [95%CI 1.13–2.32; P = 0.009]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 6.30 [95%CI 1.89–21.2; P = 0.003]). Lower body bone stress injury incidence was higher for participants within the lowest versus highest quartile of 24,25(OH)2D (OR: 4.02 [95%CI 1.82–8.87; P < 0.001]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 22.08 [95%CI 3.26–149.4; P = 0.001]), after controlling for the same covariates. Greater conversion of 25(OH)D to 24,25(OH)2D, relative to 1,25(OH)2D (i.e., low 1,25(OH)2D:24,25(OH)2D), and higher serum 24,25(OH)2D were associated with a lower incidence of lower body overuse musculoskeletal and bone stress injury. Serum 24,25(OH)2D may have a role in preventing overuse injury in young adults undertaking arduous physical training

Distal tibial bone properties and bone stress injury risk in young men undergoing arduous physical training

Trabecular microarchitecture contributes to bone strength, but its role in bone stress injury (BSI) risk in young healthy adults is unclear. Tibial volumetric BMD (vBMD), geometry, and microarchitecture, whole-body areal BMD, lean and fat mass, biochemical markers of bone metabolism, aerobic fitness, and muscle strength and power were measured in 201 British Army male infantry recruits (age 20.7 [4.3] years, BMI 24.0 ± 2.7 kg·m2) in week one of basic training. Tibial scans were performed at the ultra-distal site, 22.5 mm from the distal endplate of the non-dominant leg using High Resolution Peripheral Quantitative Computed Tomography (XtremeCT, Scanco Medical AG, Switzerland). Binary logistic regression analysis was performed to identify associations with lower body BSI confirmed by MRI. 20 recruits (10.0%) were diagnosed with a lower body BSI. Pre-injured participants had lower cortical area, stiffness and estimated failure load (p = 0.029, 0.012 and 0.011 respectively) but tibial vBMD, geometry, and microarchitecture were not associated with BSI incidence when controlling for age, total body mass, lean body mass, height, total 25(OH)D, 2.4-km run time, peak power output and maximum dynamic lift strength. Infantry Regiment (OR 9.3 [95%CI, 2.6, 33.4]) Parachute versus Line Infantry, (p ≤ 0.001) and 2.4-km best effort run time (1.06 [95%CI, 1.02, 1.10], p < 0.033) were significant predictors. Intrinsic risk factors, including ultradistal tibial density, geometry, and microarchitecture, were not associated with lower body BSI during arduous infantry training. The ninefold increased risk of BSI in the Parachute Regiment compared with Line Infantry suggests that injury propensity is primarily a function of training load and risk factors are population-specific

Measurements of the UV background at 4.6 < z < 6.4 using the quasar proximity effect

We present measurements of the ionising ultraviolet background (UVB) at z ~ 5-6 using the quasar proximity effect. The fifteen quasars in our sample cover the range 4.6 < z_q < 6.4, enabling the first proximity effect measurements of the UVB at z > 5. The metagalactic hydrogen ionisation rate, Gamma_bkg, was determined by modelling the combined ionisation field from the quasar and the UVB in the proximity zone on a pixel-by-pixel basis. The optical depths in the spectra were corrected for the expected effect of the quasar until the mean flux in the proximity region equalled that in the average Ly-alpha forest, and from this we make a measurement of Gamma_bkg. A number of systematic effects were tested using synthetic spectra. Noise in the flux was found to be the largest source of bias at z ~ 5, while uncertainties in the mean transmitted Ly-alpha flux are responsible for the largest bias at z ~ 6. The impacts of large-scale overdensities and Lyman limit systems on Gamma_bkg were also investigated, but found to be small at z > 5. We find a decline in Gamma_bkg with redshift, from log(Gamma_bkg) = -12.15 $\pm$ 0.16 at z ~ 5 to log(Gamma_bkg) = -12.84 $\pm$ 0.18 at z ~ 6 (1 sigma errors). Compared to UVB measurements at lower redshifts, our measurements suggest a drop of a factor of five in the HI photoionisation rate between z ~ 4 and z ~ 6. The decline of Gamma_bkg appears to be gradual, and we find no evidence for a sudden change in the UVB at any redshift that would indicate a rapid change in the attenuation length of ionising photons. Combined with recent measurements of the evolution of the mean free path of ionising photons, our results imply decline in the emissivity of ionising photons by roughly a factor of two from z ~ 5 to 6, albeit with significant uncertainty due to the measurement errors in both Gamma_bkg and the mean free path.Comment: 22 pages, 19 figures, 5 tables; accepted for publication in MNRA

Evidence for Reionization at z ~ 6: Detection of a Gunn-Peterson Trough in a z=6.28 Quasar

We present moderate resolution Keck spectroscopy of quasars at z=5.82, 5.99 and 6.28, discovered by the Sloan Digital Sky Survey (SDSS). We find that the Ly Alpha absorption in the spectra of these quasars evolves strongly with redshift. To z~5.7, the Ly Alpha absorption evolves as expected from an extrapolation from lower redshifts. However, in the highest redshift object, SDSSp J103027.10+052455.0 (z=6.28), the average transmitted flux is 0.0038+-0.0026 times that of the continuum level over 8450 A < lambda < 8710 A (5.95<z(abs)<6.16), consistent with zero flux. Thus the flux level drops by a factor of >150, and is consistent with zero flux in the Ly Alpha forest region immediately blueward of the Ly Alpha emission line, compared with a drop by a factor of ~10 at z(abs)~5.3. A similar break is seen at Ly Beta; because of the decreased oscillator strength of this transition, this allows us to put a considerably stronger limit, tau(eff) > 20, on the optical depth to Ly Alpha absorption at z=6. This is a clear detection of a complete Gunn-Peterson trough, caused by neutral hydrogen in the intergalactic medium. Even a small neutral hydrogen fraction in the intergalactic medium would result in an undetectable flux in the Ly Alpha forest region. Therefore, the existence of the Gunn-Peterson trough by itself does not indicate that the quasar is observed prior to the reionization epoch. However, the fast evolution of the mean absorption in these high-redshift quasars suggests that the mean ionizing background along the line of sight to this quasar has declined significantly from z~5 to 6, and the universe is approaching the reionization epoch at z~6.Comment: Revised version (2001 Sep 4) accepted by the Astronomical Journal (minor changes

Influence of vitamin D supplementation by sunlight or oral D3 on exercise performance

Purpose: To determine the relationship between vitamin D status and exercise performance in a large, prospective cohort study of young men and women across seasons (Study-1). Then, in a randomized, placebo-controlled trial, to investigate the effects on exercise performance of achieving vitamin D sufficiency (serum 25(OH)D ≥ 50 nmol·L-1) by a unique comparison of safe, simulated-sunlight and oral vitamin D3 supplementation in wintertime (Study-2).  Methods: In Study-1, we determined 25(OH)D relationship with exercise performance in 967 military recruits. In Study-2, 137 men received either placebo, simulated-sunlight (1.3x standard erythemal dose in T-shirt and shorts, three-times-per-week for 4-weeks and then once-per-week for 8-weeks) or oral vitamin D3 (1,000 IU[BULLET OPERATOR]day-1 for 4-weeks and then 400 IU[BULLET OPERATOR]day-1 for 8-weeks). We measured serum 25(OH)D by LC-MS/MS and endurance, strength and power by 1.5-mile run, maximum-dynamic-lift and vertical jump, respectively.  Results: In Study-1, only 9% of men and 36% of women were vitamin D sufficient during wintertime. After controlling for body composition, smoking and season, 25(OH)D was positively associated with endurance performance (P ≤ 0.01, [INCREMENT]R2 = 0.03–0.06, small f2 effect sizes): 1.5-mile run time was ~half-a-second faster for every 1 nmol·L-1 increase in 25(OH)D. No significant effects on strength or power emerged (P > 0.05). In Study-2, safe simulated-sunlight and oral vitamin D3 supplementation were similarly effective in achieving vitamin D sufficiency in almost all (97%); however, this did not improve exercise performance (P > 0.05).  Conclusion: Vitamin D status was associated with endurance performance but not strength or power in a prospective cohort study. Achieving vitamin D sufficiency via safe, simulated summer sunlight or oral vitamin D3 supplementation did not improve exercise performance in a randomized-controlled trial

Testing cosmological variability of the proton-to-electron mass ratio using the spectrum of PKS 0528-250

Multidimensional cosmologies allow for variations of fundamental physical constants over the course of cosmological evolution, and different versions of the theories predict different time dependences. In particular, such variations could manifest themselves as changes of the proton-to-electron mass ratio \mu=m_p/m_e over the period of ~ 10^{10} years since the moment of formation of high-redshift QSO spectra. Here we analyze a new, high-resolution spectrum of the z=2.81080 molecular hydrogen absorption system toward the quasar PKS 0528-250 to derive a new observational constraint to the time-averaged variation rate of the proton-to-electron mass ratio. We find |\dot{\mu} / \mu| < 1.5 \times 10^{-14}/year, which is much tighter than previously measured limits.Comment: 9 pages, 2 tables, 3 figures, LaTeX (aas2pp4.sty and epsf.sty included). To be published in Ap

A Submillimetre Selected Quasar in the Field of Abell478

We present the discovery of a dusty quasar, SMMJ04135+10277, located behind the galaxy cluster Abell 478. The quasar was discovered as the brightest source in a submillimetre survey of high redshift galaxies lensed by foreground rich clusters of galaxies in a project aimed at studying the cosmic star formation history of dusty galaxies. With submm fluxes of S_850 = 25+-2.8 mJy and S_450 = 55+-17 mJy this object is one of the brightest submillimetre sources known. Optical observations revealed a quasar with redshift z=2.837. The quasar was also detected at shorter infrared wavelengths with the Infrared Space Observatory. This object is the first quasar discovered by its submm emission. Given the general lack of overlap between deep submm and X-ray samples, usually interpreted as a low incidence of active nuclei in submm samples, this is an unusual object. Analysis of number counts of quasars and of submm galaxies bears out this suggestion. We compare the properties of SMMJ04135+10277 to those of optically selected quasars with submm emission, and argue that the optical faintness results from a large viewing angle with the direction of relativistic beaming, and not from abnormally high extinction. We also find indications that the bulk of the submm flux density is not powered by the quasar nucleus. This conclusion is supported by analysis of the infrared spectral energy distribution. These results are consistent with previous observations that quasars at higher redshift tend to have a more prominent cold dust component, most likely powered by extended star formation in the host galaxy. The quasar is found to have a total infrared luminosity of (2.9+-0.5)x10^13 L_sun, dominated by the emission from cool dust. (Abridged)Comment: 8 pages, 4 figures. Accepted for publication in A&

Sex differences in iron status during military training:A prospective cohort study of longitudinal changes and associations with endurance performance and musculoskeletal outcomes

This study investigated sex differences in iron status, and associations between iron status and endurance and musculoskeletal outcomes, in military training. 2,277 British Army trainees (581 women) participated. Iron markers and endurance performance (2.4 km run) were measured at the start (week 1) and end (week 13) of training. Whole-body areal body mineral density (aBMD) and markers of bone metabolism were measured at week 1. Injuries during training were recorded. Training decreased haemoglobin in men and women (mean change [95% CI], −0.1 [−0.2, −0.0] and −0.7 [−0.9, −0.6] g∙dL-1, both p < 0.001), but more so in women (p < 0.001). Ferritin decreased in men and women (−27 [−28, −23] and −5 [−8, −1] ug∙L, both p ≤ 0.001), but more so in men (p < 0.001). sTfR increased in men and women (2.9 [2.3, 3.6] and 3.8 [2.7, 4.9] nmol∙L, both p < 0.001), with no difference between sexes (p = 0.872). RDW increased in men (0.3 [0.2, 0.4]%, p < 0.001), but not women (0.1 [−0.1, 0.2]%, p = 0.956). MCV decreased in men (−1.5 [−1.8, −1.1] fL, p < 0.001), but not women (0.4 [−0.4, 1.3] fL, p = 0.087). Lower ferritin was associated with slower 2.4 km run time (p = 0.018), sustaining a lower limb overuse injury (p = 0.048), lower aBMD (p = 0.021), and higher βCTX and P1NP (both p < 0.001) controlling for sex. Improving iron stores before training may protect haemoglobin in women and improve endurance and protect against injury