Ignorability Conditions for incomplete Data and the First-Order Markov Conditional Linear Expectation Approach for Analysis of Longitudinal Discrete Data With Overdispersion

Medical researchers strive to collect complete information, but most studies will have some degree of missing data. We first study the situations in which we can relax well accepted conditions under which inferences that ignore missing data are valid. We partition a set of data into outcome, conditioning, and latent variables, all of which potentially affect the probability of a missing response. We describe sufficient conditions under which a complete-case estimate of the conditional cumulative distribution function of the outcome given the conditioning variable is unbiased. We use simulations on a renal transplant data set to illustrate the implications of these results. After describing when missing data can be ignored, we provide a likelihood based statistical approach that accounts for missing data in longitudinal studies, by fitting correlation structures that are plausible for measurements that may be unbalanced and unequally spaced in time. Our approach can be viewed as an extension of generalized linear models for longitudinal data that is in contrast to the generalized estimating equation approach that is semi-parametric. Key assumptions of our method include first-order ante-dependence within subjects; independence between subjects; exponential family distributions for the first outcome on each subject and for the subsequent conditional distributions; and linearity of the expectations of the conditional distributions. Our approach is appropriate for data with over-dispersion, which occurs when the variance is inflated relative to the assumed distribution. We consider a clinical trial to compare two treatments for seizures in patients using Poisson or Negative Binomial distributions. Next, we consider a study that evaluates the likelihood that a transplant center is flagged for poor performance using the Binomial distribution. For both studies, we perform simulations to assess the properties of our estimators and to compare our approach with GEE. We demonstrate that our method outperforms GEE, especially as the degree of overdispersion increases. We also provide software in R so that the interested reader can implement our method in his or her own analysis

Mock galaxy redshift catalogues from simulations: implications for Pan-STARRS1

We describe a method for constructing mock galaxy catalogues which are well suited for use in conjunction with large photometric surveys. We use the semi-analytic galaxy formation model of Bower et al. implemented in the Millennium simulation. We apply our method to the specific case of the surveys soon to commence with PS1, the first of 4 telescopes planned for the Pan-STARRS system. PS1 has 5 photometric bands (grizy), and will carry out an all-sky 3pi survey and a medium deep survey (MDS) over 84 sq.deg. We calculate the expected magnitude limits for extended sources in the two surveys. We find that, after 3 years, the 3pi survey will have detected over 10^8 galaxies in all 5 bands, 10 million of which will lie at redshift z>0.9, while the MDS will have detected over 10^7 galaxies with 0.5 million lying at z>2. These numbers at least double if detection in the shallowest band, y is not required. We then evaluate the accuracy of photometric redshifts estimated using an off-the-shelf photo-z code. With the grizy bands alone it is possible to achieve an accuracy in the 3pi survey of Delta z/(1+z)~0.06 for 0.25<z<0.8, which could be reduced by about 15% using near infrared photometry from the UKIDDS survey, but would increase by about 25% for the deeper sample without the y band photometry. For the MDS an accuracy of Delta z/(1+z)~0.05 is achievable for 0.02<z<1.5 using grizy. A dramatic improvement in accuracy is possible by selecting only red galaxies. In this case, Delta z/(1+z)~0.02-0.04 is achievable for ~100 million galaxies at 0.4<z<1.1 in the 3pi survey and for 30 million galaxies in the MDS at 0.4<z<2. We investigate the effect of using photo-z in the estimate of the baryonic acoustic oscillation scale. We find that PS1 will achieve a similar accuracy in this estimate as a spectroscopic survey of 20 million galaxies.Comment: 23 pages, 18 figures, accepted by MNRA

The Extragalactic Distance Scale Key Project XXVII. A Derivation of the Hubble Constant Using the Fundamental Plane and Dn-Sigma Relations in Leo I, Virgo, and Fornax

Using published photometry and spectroscopy, we construct the fundamental plane and D_n-Sigma relations in Leo I, Virgo and Fornax. The published Cepheid P-L relations to spirals in these clusters fixes the relation between angular size and metric distance for both the fundamental plane and D_n-Sigma relations. Using the locally calibrated fundamental plane, we infer distances to a sample of clusters with a mean redshift of cz \approx 6000 \kms, and derive a value of H_0=78+- 5+- 9 km/s/Mpc (random, systematic) for the local expansion rate. This value includes a correction for depth effects in the Cepheid distances to the nearby clusters, which decreased the deduced value of the expansion rate by 5% +- 5%. If one further adopts the metallicity correction to the Cepheid PL relation, as derived by the Key Project, the value of the Hubble constant would decrease by a further 6%+- 4%. These two sources of systematic error, when combined with a +- 6% error due to the uncertainty in the distance to the Large Magellanic Cloud, a +- 4% error due to uncertainties in the WFPC2 calibration, and several small sources of uncertainty in the fundamental plane analysis, combine to yield a total systematic uncertainty of +- 11%. We find that the values obtained using either the CMB, or a flow-field model, for the reference frame of the distant clusters, agree to within 1%. The Dn-Sigma relation also produces similar results, as expected from the correlated nature of the two scaling relations. A complete discussion of the sources of random and systematic error in this determination of the Hubble constant is also given, in order to facilitate comparison with the other secondary indicators being used by the Key Project.Comment: 21 pages, 3 figures, Accepted for publication in Ap

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

Funder: Boehringer Ingelheim; doi: http://dx.doi.org/10.13039/100001003BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009)

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc