Model selection for prognostic time-to-event gene signature discovery with applications in early breast cancer data

Model selection between competing models is a key consideration in the discovery of prognostic multigene signatures. The use of appropriate statistical performance measures as well as verification of biological significance of the signatures is imperative to maximise the chance of external validation of the generated signatures. Current approaches in time-to-event studies often use only a single measure of performance in model selection, such as logrank test p-values, or dichotomise the follow-up times at some phase of the study to facilitate signature discovery. In this study we improve the prognostic signature discovery process through the application of the multivariate partial Cox model combined with the concordance index, hazard ratio of predictions, independence from available clinical covariates and biological enrichment as measures of signature performance. The proposed framework was applied to discover prognostic multigene signatures from early breast cancer data. The partial Cox model combined with the multiple performance measures were used in both guiding the selection of the optimal panel of prognostic genes and prediction of risk within cross validation without dichotomising the follow-up times at any stage. The signatures were successfully externally cross validated in independent breast cancer datasets, yielding a hazard ratio of 2.55 [1.44, 4.51] for the top ranking signature.

Geochemical records of palaeoenvironmental controls on peat forming processes in the Mfabeni peatland, Kwazulu Natal, South Africa since the Late Pleistocene

The Mfabeni peatland is the only known sub-tropical coastal fen that transcends the Last Glacial Maximum (LGM). This ca. 10m thick peat sequence provides a continuous sedimentation record spanning from the late Pleistocene to present (basal age c. 47kcalyr BP). We investigated the paleaeoenvironmental controls on peat formation and organic matter source input at the Mfabeni fen by: 1) exploring geochemical records (mass accumulation rate, total organic carbon, carbon accumulation rate, δC, δN and C/N ratio) to delineate primary production, organic matter source input, preservation and diagenetic processes, and 2) employ these geochemical signatures to reconstruct the palaeoenvironmental conditions and prevailing climate that drove carbon accumulation in the peatland. We established that the Mfabeni peat sediments have undergone minimal diagenetic alteration. The peat sequence was divided into 5 linear sedimentation rate (LSR) stages indicating distinct changes in climate and hydrological conditions: LSR stage 1 (c. 47 to c. 32.2kcalyr BP): predominantly cool and wet climate with C4 plant assemblages, interrupted by two short warming events. LSR stage 2 (c. 32.2 to c. 27.6kcalyr BP): dry and windy climate followed by a brief warm and wet period with increased C4 sedge swamp vegetation. LSR stage 3 (c. 27.6 to c. 20.3kcalyr BP): initial cool and wet period with prevailing C4 sedge plant assemblage until c. 23kcalyr BP; then an abrupt change to dry and cool glacial conditions and steady increases in C3 grasses. LSR stage 4 (c. 20.3 to c. 10.4kcalyr BP): continuation of cool and dry conditions and strong C3 grassland signature until c. 15kcalyr BP, after which precipitation increases. LSR stage 5 (c. 10.4kcalyr BP to present): characterised by extreme fluctuations between pervasive wet and warm to cool interglacial conditions with intermittent abrupt millennial-scale cooling/drying events and oscillations between C3 and C4 plant assemblages. In this study we reconstructed a high-resolution record of local hydrology, bulk plant assemblage and inferred climate since the Late Pleistocene, which suggest an anti-phase link between Southern African and the Northern Hemisphere, most notably during Heinrich (5 to 2) and Younger Dryas events. © 2013 Elsevier B.V.

Neonatal intensive care and late preterm infants:Health and family functioning at three years

Background: Late preterm infants (LPIs), born at 34 + 0 to 36 + 6 weeks of gestation contribute a significant proportion of all neonatal intensive care (NIC) admissions and are regarded as being at risk of adverse outcomes compared to term-born infants.

Aim: To explore the health outcomes and family functioning of LPIs who required neonatal intensive care, at three years of age.

Study design and subjects: This cohort study included 225 children born late preterm, between 1 January and 31 December 2006 in Northern Ireland. Children admitted for NIC (study group, n = 103) were compared with children who did not require NIC or who required special care only for up to three days (comparison group, n = 122).

Outcome measures
Health outcomes were measured using the Health Status Questionnaire, health service usage by parent report and family functioning using the PedsQL™ Family Impact Module.

Results: LPIs who required NIC revealed similar health outcomes at three years in comparison to those who did not. Despite this, more parents of LPIs who required NIC reported visiting their GP and medical specialists during their child's third year of life. Differences in family functioning were also observed with mothers of LPIs who required NIC reporting, significantly lower levels of social and physical functioning, increased difficulties with communication and increased levels of worry.

Conclusions: LPIs were observed to have similar health outcomes at three years of age regardless of NIC requirement. The increase in GP and medical specialist visits and family functioning difficulties observed among those infants who required NIC merits further investigation.

Abbreviations: LPI, late preterm infant; NIC, neonatal intensive care; HSQ, Health Status Questionnaire; GP, general practitioner

Middle to late Holocene chironomid-inferred July temperatures for the central Northwest Territories, Canada

We analyzed subfossil chironomids, sediment organic matter and sediment particle size data from a 1.11-m-long freeze core collected from Carleton Lake (unofficial name), located approximately 120 km north of the modern treeline. This well-dated core spans the last ca. 6,500 years. Two chironomid transfer functions were applied to infer mean July air temperatures. Our results indicated that the chironomid-inferred temperatures from this lake sediment record did not pass a significance test, suggesting that other factors in addition to temperature may have been important in structuring the chironomid community through time. Although not statistically significant, the chironomid-inferred temperatures from this site do follow a familiar pattern, with highest inferred temperatures occurring during the Holocene Thermal Maximum (~6–4 cal kyr BP), followed by a long-term cooling trend, which is reversed during the last 600 years. The largest change in the chironomid assemblage, which occurred between ca. 4,600 and 3,900 cal yr BP is possibly related to the well-documented northward advance and subsequent retreat of treeline in this region.

EL CVn-type binaries - Discovery of 17 helium white dwarf precursors in bright eclipsing binary star systems

The star 1SWASP J024743.37-251549.2 was recently discovered to be a binary star in which an A-type dwarf star eclipses the remnant of a disrupted red giant star (WASP 0247-25 B). The remnant is in a rarely observed state evolving to higher effective temperatures at nearly constant luminosity prior to becoming a very low mass white dwarf composed almost entirely of helium, i.e. it is a pre-helium white dwarf (pre-He-WD). We have used the photometric database from theWide Angle Search for Planets (WASP) to find 17 eclipsing binary stars with orbital periods P = 0.7-2.2 d with similar light curves to 1SWASP J024743.37-251549.2. The only star in this group previously identified as a variable star is the brightest one, EL CVn, which we adopt as the prototype for this class of eclipsing binary star. The characteristic light curves of EL CVn-type stars show a total eclipse by an A-type dwarf star of a smaller, hotter star and a secondary eclipse of comparable depth to the primary eclipse. We have used new spectroscopic observations for six of these systems to confirm that the companions to the A-type stars in these binaries have very low masses (≈0.2M⊙). This includes the companion to EL CVn which was not previously known to be a pre-He-WD. EL CVn-type binary star systems will enable us to study the formation of very low mass white dwarfs in great detail, particularly in those cases where the pre-He-WD star shows non-radial pulsations similar to those recently discovered in WASP0247-25 B. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Impact of community based, specialist palliative care teams on hospitalisations and emergency department visits late in life and hospital deaths: a pooled analysis

Objective: To determine the pooled effect of exposure to one of 11 specialist palliative care teams providing services in patients’ homes.Design: Pooled analysis of a retrospective cohort study.Setting: Ontario, Canada.Participants: 3109 patients who received care from specialist palliative care teams in 2009-11 (exposed) matched by propensity score to 3109 patients who received usual care (unexposed).Intervention: The palliative care teams studied served different geographies and varied in team composition and size but had the same core team members and role: a core group of palliative care physicians, nurses, and family physicians who provide integrated palliative care to patients in their homes. The teams’ role was to manage symptoms, provide education and care, coordinate services, and be available without interruption regardless of time or day.Main outcome measures: Patients (a) being in hospital in the last two weeks of life; (b) having an emergency department visit in the last two weeks of life; or (c) dying in hospital.Results: In both exposed and unexposed groups, about 80% had cancer and 78% received end of life homecare services for the same average duration. Across all palliative care teams, 970 (31.2%) of the exposed group were in hospital and 896 (28.9%) had an emergency department visit in the last two weeks of life respectively, compared with 1219 (39.3%) and 1070 (34.5%) of the unexposed group (P<0.001). The pooled relative risks of being in hospital and having an emergency department visit in late life comparing exposed versus unexposed were 0.68 (95% confidence interval 0.61 to 0.76) and 0.77 (0.69 to 0.86) respectively. Fewer exposed than unexposed patients died in hospital (503 (16.2%) v 887 (28.6%), P<0.001), and the pooled relative risk of dying in hospital was 0.46 (0.40 to 0.52).Conclusions: Community based specialist palliative care teams, despite variation in team composition and geographies, were effective at reducing acute care use and hospital deaths at the end of life.

The progenitor mass of the Type IIP supernova SN 2004et from late-time spectral modeling

SN 2004et is one of the nearest and best-observed Type IIP supernovae, with a progenitor detection as well as good photometric and spectroscopic observational coverage well into the nebular phase. Based on nucleosynthesis from stellar evolution/explosion models we apply spectral modeling to analyze its 140-700 day evolution from ultraviolet to mid-infrared. We find a M_ZAMS= 15 Msun progenitor star (with an oxygen mass of 0.8 Msun) to satisfactorily reproduce [O I] 6300, 6364 {\AA} and other emission lines of carbon, sodium, magnesium, and silicon, while 12 Msun and 19 Msun models under- and overproduce most of these lines, respectively. This result is in fair agreement with the mass derived from the progenitor detection, but in disagreement with hydrodynamical modeling of the early-time light curve. From modeling of the mid-infrared iron-group emission lines, we determine the density of the "Ni-bubble" to rho(t) = 7E-14*(t/100d)^-3 g cm^-3, corresponding to a filling factor of f = 0.15 in the metal core region (V = 1800 km/s). We also confirm that silicate dust, CO, and SiO emission are all present in the spectra.

Behavioural outcomes at 3 years of age among late preterm infants admitted to neonatal intensive care: a cohort study

Objective: Examine the behavioural outcomes at age 3 years of late preterm infants (LPIs) who were admitted to neonatal intensive care (NIC) in comparison with LPIs who were not admitted.
Method: This cohort study prospectively recruited 225 children born late preterm (34–36+6 weeks gestation) in 2006 in Northern Ireland, now aged 3 years. Two groups were compared: LPIs who received NIC (study; n=103) and LPIs who did not receive NIC (control; n=122). Parents/guardians completed the Child Behaviour Checklist/1½-5. Descriptive maternal and infant data were also collected.
Results: As expected LPI children admitted to NIC had higher medical risk than the non-admitted comparison group (increased caesarean section, born at earlier gestation, lower birth weight and an episode of resuscitation at birth). LPIs admitted to NIC scored higher on the Child Behaviour Checklist/1½-5 compared with those who were not admitted indicating more behavioural problems; this was statistically significant for the Aggressive Behaviour Subscale (z=−2.36) and the Externalising Problems Scale (z=−2.42). The group difference on the Externalising Problems Scale was no longer significant after controlling for gender, gestational age and deprivation score.
Conclusions: This study provides valuable data on the behaviour at age 3 years of LPIs admitted to NIC compared with LPIs not admitted to NIC. Further research would be beneficial to explore medical and psychosocial explanations for observed differences between groups using large prospective cohort studies.

A Late Pleistocene record of climate and environmental change from the northern and southern Kelabit Highlands of Sarawak, Malaysian Borneo

A late Pleistocene vegetation record is presented, using multi-proxy analysis from three palaeochannels in the northern (Bario) and southern (Pa'Dalih) Kelabit Highlands of Sarawak, Malaysian Borneo. Before 50 000 cal a BP and until approximate to 47 700 cal a BP [marine isotope stage 3 (MIS3)], two of the sites were probably being influenced by energetic fluvial deposition, possibly associated with strong seasonality. Fluvial activity declines between 47 700 and 30 000 cal a BP (MIS3), and may be associated with a reduction in seasonality with overall stability in precipitation. The pollen record between 47 700 and 30 000 cal a BP generally shows much higher representation of upper-montane taxa compared with the Holocene, indicating often significantly reduced temperatures. After 35 000-30 000 cal a BP and until the mid-Holocene, hiatuses appear in two of the records, which could be linked to fluvial down-cutting during the late/mid Holocene. Despite the jump in ages, a pronounced representation of Ericaceae and upper-montane taxa, represented both at Bario and at Pa'Dalih, corresponds to a further lowering of temperatures during the Last Glacial Maximum (MIS2). Thick charcoal bands in the PDH 210 record also suggest periods of extreme aridity between 30 200 and 12 700 cal a BP. This is followed by energetic fluvial deposition of sands and gravels, and may reflect a significant increase in seasonality.

The late effects of cancer and cancer treatment:a rapid review

This paper aims to synthesize literature about the definition, prevalence, onset and treatments associated with late effects. A rapid review was conducted using Google Scholar to identify reviews related to the late effects of adult-onset cancers. Papers were included if they provided a definition of late effects and/or presented a review of late effects as a result of adult-onset cancers in patients aged 18 years or older. Reviews related to nonmelanoma skin cancer were excluded. Reviews focusing on late effects in survivors of childhood-onset cancers (younger than 18 years) were ineligible for inclusion in the review. A total of 16 reviews were identified. Between 0% and 100% of survivors experienced a range of physical, psychological and social late effects. The onset of physical late effects was defined broadly as 'months or years' after treatment, whereas psychological late effects were defined as occurring at the end of treatment or similarly to physical late effects as 'months or years' after treatment. Few reviews provided an operational definition of late effects, and the onset of late effects was not often reported. Thus, reviews may have included the acute and long-term effects of cancer treatment. Evidence regarding causes, prevalence, and onset was incomplete for many late effects. Understanding the cause and onset of late effects is important in order to provide timely interventions to reduce the risk of late effect development in cancer patients.

Human Resource Management in Multinational Enterprises: Evidence From a Late Industrializing Economy

This paper examines the extent to which human resource management (HRM) practices in multinational enterprises (MNEs) from a small, late developing and highly globalized economy resemble their counterparts from larger, early industrializing countries. The paper draws on data from a large-scale representative survey of 260 MNEs in Ireland. The results demonstrate that there are significant differences between the HRM practices deployed in Irish-owned MNEs and that of their US counterparts but considerable similarity with UK firms. A key conclusion is that arguments in the literature regarding MNEs moving towards the adoption of global best practices, equating to the pursuance of an American model of HRM, were not obvious. The study found considerable variation from ‘US practices’ amongst indigenous Irish MNEs.

Main-belt Comet P/2012 T1 (PANSTARRS)

We present initial results from observations and numerical analyses aimed at characterizing the main-belt comet P/2012 T1 (PANSTARRS). Optical monitoring observations were made between 2012 October and 2013 February using the University of Hawaii 2.2 m telescope, the Keck I telescope, the Baade and Clay Magellan telescopes, Faulkes Telescope South, the Perkins Telescope at Lowell Observatory, and the Southern Astrophysical Research Telescope. The object's intrinsic brightness approximately doubles from the time of its discovery in early October until mid-November and then decreases by ~60% between late December and early February, similar to photometric behavior exhibited by several other main-belt comets and unlike that exhibited by disrupted asteroid (596) Scheila. We also used Keck to conduct spectroscopic searches for CN emission as well as absorption at 0.7 μm that could indicate the presence of hydrated minerals, finding an upper limit CN production rate of Q CN <1.5 × 1023 mol s-1, from which we infer a water production rate of Q_H_2O100 Myr and is unlikely to be a recently implanted interloper from the outer solar system, while a search for potential asteroid family associations reveals that it is dynamically linked to the ~155 Myr old Lixiaohua asteroid family. Some of the data presented herein were obtained at the W. M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California, and the National Aeronautics and Space Administration, and made possible by the generous financial support of the W. M. Keck Foundation, the Magellan Telescopes located at Las Campanas Observatory, Chile, and the Southern Astrophysical Research (SOAR) telescope, which is a joint project of the Ministério da Ciência, Tecnologia, e Inovação (MCTI) da República Federativa do Brasil, the U.S. National Optical Astronomy Observatory (NOAO), the University of North Carolina at Chapel Hill (UNC), and Michigan State University (MSU).