Generalizing trial evidence to target populations in non-nested designs: Applications to AIDS clinical trials

Comparative effectiveness evidence from randomized trials may not be directly generalizable to a target population of substantive interest when, as in most cases, trial participants are not randomly sampled from the target population. Motivated by the need to generalize evidence from two trials conducted in the AIDS Clinical Trials Group (ACTG), we consider weighting, regression and doubly robust estimators to estimate the causal effects of HIV interventions in a specified population of people living with HIV in the USA. We focus on a non-nested trial design and discuss strategies for both point and variance estimation of the target population average treatment effect. Specifically in the generalizability context, we demonstrate both analytically and empirically that estimating the known propensity score in trials does not increase the variance for each of the weighting, regression and doubly robust estimators. We apply these methods to generalize the average treatment effects from two ACTG trials to specified target populations and operationalize key practical considerations. Finally, we report on a simulation study that investigates the finite-sample operating characteristics of the generalizability estimators and their sandwich variance estimators

Regulation, sensory domains and roles of two Desulfovibrio desulfuricans ATCC27774 Crp family transcription factors, HcpR1 and HcpR2, in response to nitrosative stress

In silico analyses identified a Crp/Fnr family transcription factor (HcpR) in sulfate-reducing bacteria that controls expression of the hcp gene, which encodes the hybrid cluster protein and contributes to nitrosative stress responses. There is only one hcpR gene in the model sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough, but two copies in D. desulfuricans 27774, which can use nitrate as an alternative electron acceptor to sulfate. Structures of the D. desulfuricans hcpR1, hcpR2 and hcp operons are reported. We present evidence that hcp expression is regulated by HcpR2, not by HcpR1, and that these two regulators differ in both their DNA-binding site specificity and their sensory domains. HcpR1 is predicted to be a b-type cytochrome. HcpR1 binds upstream of the hcpR1 operon and its synthesis is regulated coordinately with hcp in response to NO. In contrast, hcpR2 expression was not induced by nitrate, nitrite or NO. HcpR2 is an iron-sulfur protein that reacts with NO and O2 . We propose that HcpR1 and HcpR2 use different sensory mechanisms to regulate subsets of genes required for defense against NO-induced nitrosative stress, and that diversification of signal perception and DNA recognition by these two proteins is a product of D. desulfuricans adaptation to its particular environmental niche. This article is protected by copyright. All rights reserved

The Authors Respond

We welcome the discussion by Huitfeldt and Stensrud on our recent article on generalizing study results. One assumption we listed in the set of sufficient conditions for generalizability was exchangeability between the study sample and the target population, perhaps conditional on a set of covariate

Evaluating G2G for use in Rapid Response Catchments: Final Report

Flood impacts can be severe for rapid response catchments (RRCs). Providing targeted flood warnings is challenging using existing methodologies and on account of the typical absence of river flow gauging. The Pitt Review of the Summer 2007 floods recognised the need for new alert procedures for RRCs able to exploit the new distributed flood forecasting capability being progressed from research into operations. Work on the G2G (Grid-to-Grid) distributed hydrological model was accelerated into operational practice to support 5-day countrywide flood outlooks, a major recommendation of the Pitt Review. The present study aims to explore the potential of G2G to support more frequent and detailed alerts relevant to flood warning in RRCs. Integral to this study is the use of emerging rainfall forecast products, in deterministic and ensemble form, which allow the lead-time of G2G flow forecasts to be extended and given an uncertainty context. This Report sets down the overall scope of the project, provides an introduction to G2G by way of background and then reports on the outcomes of the R&D study. This includes extensive preparatory work on collating historical datasets to support G2G model assessment, both relating to hydrometry and new rainfall forecast products. A framework is developed for assessing G2G in both simulation-mode and forecast-mode (as a function of lead-time) targeted at the RRC requirement. Relevant to the requirement is the RRC Register of points and areas of interest compiled by the Environment Agency, and the characteristics of RRCs (occurring in isolation or in combination): small catchment area, urban/sub-urban land-cover and steep slopes. The assessment framework is first applied assuming perfect knowledge of rainfall observations for past and future times, so as not to confound the analysis with errors from rainfall forecasts. Variability of performance measures across groups of sites is summarised through box and whisker plots, groups being differentiated on size of catchment area and nature of G2G run (simulation, and with the addition of state updating and flow insertion in turn). Skill scores judge how well the model performs in detecting a flood event exceeding a flow threshold, taken as the median annual flood (as an indicator of bankfull flow exceedance for natural channels) and fractional multipliers of it. The skill scores include POD (Probability of Detection) and FAR (False Alarm Ratio). Performance maps of R2 Efficiency, indicating the variability in the observations accounted for by the model, are used to portray the spatial variability of G2G accuracy across the country. G2G performance in small catchments, relevant to the RRC requirement, is best over South West, North East and North West regions; also median performance appears robust from one year to the next. Larger catchments benefit most in forecast-mode from flow insertion, whilst smaller headwater catchments gain particularly from ARMA (AutoRegressive Moving Average) error-prediction. An assessment is made of using deterministic rainfall forecasts from NWP UKV - the Numerical Weather Prediction UK Variable Resolution form of the Met Office Unified Model - in a full emulation of G2G in real-time, and using foreknowledge of rainfall observations as a reference baseline. Forecast quality can deteriorate strongly beyond 12 hours, especially for smaller catchments, whilst for some locations good performance is maintained even for long lead-times. Diagnostic analysis reveals that the UKV rainfall forecasts have patterns of overestimation in some lowland areas (e.g. over London) and leeward of high elevation areas (e.g. north and south Pennines). Overall performance is better in Scotland although there is evidence of UKV overestimating rainfall near the coast at Edinburgh and Elgin in the north. The assessment framework is extended to include rainfall forecast ensembles and probabilistic flood forecasting, using a combination of case-study and longer-term analyses. Blended Ensemble rainfall forecasts are assessed in two forms: forecasts out to 24 hours updated 4 times a day, and nowcasts out to 7 hours updated every 15 minutes. The 24 hour forecasts generally perform well as input to G2G in the case studies, the G2G flow forecasts typically signalling a flood peak 12 to 18 hours in advance and ahead of any observed response for small catchments. New regional summary map displays of the probability of flow threshold exceedances over a forecast horizon, and for increasing levels of severity, are developed to highlight evolving hotspots of flood risk over time. The first ever continuous assessment of G2G probability flow forecasts is reported using national maps of probabilistic skill scores - Relative Operating Characteristic (ROC) Skill Score and Brier Skill Score (BSS) - to spatially assess their performance. It is noted that the short periods available for assessment - a 7½ month period over England & Wales and 4 ½ months over Scotland - limit the analyses to low return period flow thresholds. Half the median (2-year) flood is used although a regional pooled analysis allows some assessment up to 5-year. The G2G probability forecast assessed is the probability of the chosen flow threshold being exceeded at any time over the forecast horizon (taken to be 24 hours). Comparison of these scores when applied to deterministic and probabilistic forecasts from G2G provides strong evidence of the value of G2G ensemble forecasts as an indicator of flood risk over Britain. Noticeably poorer performance indicated by the BSS across Scotland is in part attributed to the short, summer-dominated assessment period. Operational tools available to FFC and the SFFS for using G2G flow ensembles are reviewed and options for improvement identified drawing on the experience and findings of the study. This leads to identifying some work of an operational nature for consideration in Phase 3 of the project. The report closes with a summary of project achievements grouped thematically, a set of recommendations both of a general nature and specific to FFC and SFFS needs, and finally some proposals for consideration under Phase 3 of the G2G for Rapid Response Catchments project. Some key benefits arising from the project are summarised below. • Evidence has been produced that shows G2G has good skill in providing strategic forecasts for RRCs. The evidence is stratified by catchment type (area, urbanisation, headwater), form of forecast (simulation or forecast mode) and nature of rainfall input (raingauge, deterministic forecast, ensemble forecast). • Strong evidence has been presented on the advantage of using an ensemble rainfall forecast as input to G2G to obtain a probabilistic flood forecast for an RRC, relative to an approach where only a single deterministic rainfall and flood forecast is obtained. This indicates better guidance can be given on forecast flood risk for RRCs, improving the level of service provision for such catchments which are currently not well served. • An improved G2G model configuration, exploiting gauged flows from 912 sites and including new locally calibrated parameters, has been delivered and made operational for the FFC with England & Wales coverage. The benefit is improved operational flood forecast accuracy. For Scotland, an enhanced configuration will be delivered to SFFS in Spring 2014. • Detailed recommendations on how the visual presentation of G2G ensemble results could be improved are set down in this report. When further developed and implemented, these will prove of benefit to the preparation of Flood Guidance Statements issued by FFC and the SFFS across Britain

Generalizing Study Results: A Potential Outcomes Perspective

Great care is taken in epidemiologic studies to ensure the internal validity of causal effect estimates; however, external validity has received considerably less attention. When the study sample is not a random sample of the target population, the sample average treatment effect, even if internally valid, cannot usually be expected to equal the average treatment effect in the target population. The utility of an effect estimate for planning purposes and decision making will depend on the degree of departure from the true causal effect in the target population due to problems with both internal and external validity. Herein, we review concepts from recent literature on generalizability, one facet of external validity, using the potential outcomes framework. Identification conditions sufficient for external validity closely parallel identification conditions for internal validity, namely conditional exchangeability; positivity; the same distributions of the versions of treatment; no interference; and no measurement error. We also require correct model specification. Under these conditions, we discuss how a version of direct standardization (the g-formula, adjustment formula, or transport formula) or inverse probability weighting can be used to generalize a causal effect from a study sample to a well-defined target population, and demonstrate their application in an illustrative example

Comparative safety and health care expenditures among patients with chronic myeloid leukemia initiating first-line imatinib, dasatinib, or nilotinib

PURPOSE Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myeloid leukemia (CML). No overall survival differences were observed between patients initiating first- and second-generation TKIs in trials; however, real-world safety and cost outcomes are unclear. We evaluated comparative safety and health care expenditures between first-line imatinib, dasatinib, and nilotinib among patients with CML. PATIENTS AND METHODS Eligible patients had one or more fills for imatinib, dasatinib, or nilotinib in the MarketScan Commercial and Medicare Supplemental databases between January 1, 2011, and December 31, 2016 (earliest fill is the index date), 6 months pre-index continuous enrollment, CML diagnosis, and no TKI use in the pre-index period. Hospitalizations or emergency department visits (safety events) were compared across treatment groups using propensity-score-weighted 1-year relative risks (RRs) and subdistribution hazard ratios (HRs). Inflation-adjusted annual health care expenditures were compared using quantile regression. RESULTS Eligible patients included 1,417 receiving imatinib, 1,067 receiving dasatinib, and 647 receiving nilotinib. The 1-year risk of safety events was high: imatinib, 37%; dasatinib, 44%; and nilotinib, 40%, with higher risks among patients receiving dasatinib (RR, 1.17; 95% CI, 1.06 to 1.30) and nilotinib (RR, 1.07; 95% CI, 0.93 to 1.23) compared with those receiving imatinib. Over a median of 1.7 years, the cumulative incidence of safety events was higher among patients receiving dasatinib (HR, 1.23; 95% CI, 1.10 to 1.38) and nilotinib (HR, 1.08; 95% CI, 0.95 to 1.24) than among those receiving imatinib. One-year health care expenditures were high (median, $125,987) and were significantly higher among patients initiating second-generation TKIs compared with those receiving imatinib (difference in medians: dasatinib v imatinib,$22,393; 95% CI, $17,068 to$27,718; nilotinib v imatinib, $19,463; 95$14,689 to $24,236). CONCLUSION Patients receiving imatinib had the lowest risk of hospitalization or emergency department visits and 1-year health care expenditures. Given a lack of significant differences in overall survival, imatinib may represent the ideal first-line therapy for patients, on average

New incision rates along the Colorado River system based on cosmogenic burial dating of terraces: Implications for regional controls on Quaternary incision

New cosmogenic burial and published dates of Colorado and Green river terraces are used to infer variable incision rates along the rivers in the past 10 Ma. A knickpoint at Lees Ferry separates the lower and upper Colorado River basins. We obtained an isochron cosmogenic burial date of 1.5 ± 0.13 Ma on a 190-m-high strath terrace near Bullfrog Basin, Utah (upstream of Lees Ferry). This age yields an average incision rate of 126+12/-10m/Ma above the knickpoint and is three times older than a cosmogenic surface age on the same terrace, suggesting that surface dates inferred by exposure dating may be minimum ages. Incision rates below Lees Ferry are faster, ~170m/Ma-230m/Ma, suggesting upstream knickpoint migration over the past several million years. A terrace at Hite (above Lees Ferry) yields an isochron burial age of 0.29 ± 0.17 Ma, and a rate of ~300-900m/Ma, corroborating incision acceleration in Glen Canyon. Within the upper basin, isochron cosmogenic burial dates of 1.48 ± 0.12 Ma on a 60 m terrace near the Green River in Desolation Canyon, Utah, and 1.2 ± 0.3 Ma on a 120 m terrace upstream of Flaming Gorge, Wyoming, give incision rates of 41± 3m/Ma and 100+33/-20m/Ma, respectively. In contrast, incision rates along the upper Colorado River are 150m/Ma over 0.64 and 10 Ma time frames. Higher incision rates, gradient, and discharge along the upper Colorado River relative to the Green River are consistent with differential rock uplift of the Colorado Rockies relative to the Colorado Plateau

Statistical properties of the Burgers equation with Brownian initial velocity

We study the one-dimensional Burgers equation in the inviscid limit for Brownian initial velocity (i.e. the initial velocity is a two-sided Brownian motion that starts from the origin x=0). We obtain the one-point distribution of the velocity field in closed analytical form. In the limit where we are far from the origin, we also obtain the two-point and higher-order distributions. We show how they factorize and recover the statistical invariance through translations for the distributions of velocity increments and Lagrangian increments. We also derive the velocity structure functions and we recover the bifractality of the inverse Lagrangian map. Then, for the case where the initial density is uniform, we obtain the distribution of the density field and its $n$-point correlations. In the same limit, we derive the $n-$point distributions of the Lagrangian displacement field and the properties of shocks. We note that both the stable-clustering ansatz and the Press-Schechter mass function, that are widely used in the cosmological context, happen to be exact for this one-dimensional version of the adhesion model.Comment: 42 pages, published in J. Stat. Phy

The vulnerability of tropical peatlands to oil and gas exploration and extraction

Tropical peatlands store globally significant quantities of carbon and are ecologically and culturally important, but little is known about their vulnerability to oil and gas exploration and extraction. Here, we analyse the exposure of tropical peatlands to the activities of the petroleum industry and review what is known about the sensitivity of peatlands to these activities. We find that 8.3% (107,000 km2) of the total area of tropical peatlands overlaps with a 30-km buffer area around oil and gas infrastructure. Major areas of overlap include the Sumatra Basin (Indonesia), the Niger Delta (Nigeria) and the Putumayo-Oriente-Marañón Basin (Peru/Ecuador/Colombia). Documented environmental impacts include deforestation and habitat loss associated with the exploration and development of oil fields, and contamination from spills of oil and produced water (well brine). Peatlands, and the ecosystem services they provide, are sensitive to these impacts due to unique aspects of their ecology and hydrology, the easy spread of contamination by flowing water, the long-term storage of contaminants in peat, and the slow degradation of oil under anoxic, waterlogged conditions. Given the potential negative consequences for human health, resource security, biodiversity, and carbon storage, we propose a research agenda to provide an improved evidence base to support effective governance

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health