For right-censored data perhaps the most commonly used tests are weighted logrank tests, such as the logrank and Wilcoxon-type tests. In this paper we review several generalizations of those weighted ...logrank tests to interval-censored data and present an R package,
, to implement many of them. The
package depends on the
package, also presented here, which performs exact and asymptotic linear permutation tests. The
package performs many of the tests included in the already available
package, and provides an independent validation of
. We review analysis methods for interval-censored data, and we describe and show how to use the
and
packages.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. ...To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD “up” conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.
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•Spike-based SARS-CoV-2 vaccines potently neutralize the globally dominant G614 variant•Vaccinated and immune sera neutralize G614 better than the original spike•The structure of the G614 spike demonstrates a more open position of the RBD
Serum from SARS-CoV-2 spike-vaccinated mice, NHPs and humans, and convalescent patients, along with receptor-binding domain (RBD)-specific monoclonal antibodies neutralize the widespread G614-containing virus at greater levels than the original D614 version. Structural data demonstrate that the G614 spike is in a more open conformation with extended RBDs.
The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular ...outcomes in a large, prospective cohort of outpatients with preexisting heart failure.
We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study. Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms. More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations ( P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone ( P≤0.01 all models). There were 462 composite end points over a median 4.2 years of follow-up. In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51-19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27-2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96-5.39; P<0.001), but not in the subgroup with TSH 4.51-6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78-2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65-2.72; P<0.001).
In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis. Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.
Multiple imputation (MI) provides us with efficient estimators in model‐based methods for handling missing data under the true model. It is also well‐understood that design‐based estimators are ...robust methods that do not require accurately modeling the missing data; however, they can be inefficient. In any applied setting, it is difficult to know whether a missing data model may be good enough to win the bias‐efficiency trade‐off. Raking of weights is one approach that relies on constructing an auxiliary variable from data observed on the full cohort, which is then used to adjust the weights for the usual Horvitz‐Thompson estimator. Computing the optimally efficient raking estimator requires evaluating the expectation of the efficient score given the full cohort data, which is generally infeasible. We demonstrate MI as a practical method to compute a raking estimator that will be optimal. We compare this estimator to common parametric and semi‐parametric estimators, including standard MI. We show that while estimators, such as the semi‐parametric maximum likelihood and MI estimator, obtain optimal performance under the true model, the proposed raking estimator utilizing MI maintains a better robustness‐efficiency trade‐off even under mild model misspecification. We also show that the standard raking estimator, without MI, is often competitive with the optimal raking estimator. We demonstrate these properties through several numerical examples and provide a theoretical discussion of conditions for asymptotically superior relative efficiency of the proposed raking estimator.
Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination ...inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms.
This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a "protective" hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.
In this paper, we present a practical approach for computing the sandwich variance estimator in 2-stage regression model settings. As a motivating example for 2-stage regression, we consider ...regression calibration, a popular approach for addressing covariate measurement error. The sandwich variance approach has rarely been applied in regression calibration, despite its requiring less computation time than popular resampling approaches for variance estimation, specifically the bootstrap. This is probably because it requires specialized statistical coding. Here we first outline the steps needed to compute the sandwich variance estimator. We then develop a convenient method of computation in R for sandwich variance estimation, which leverages standard regression model outputs and existing R functions and can be applied in the case of a simple random sample or complex survey design. We use a simulation study to compare the sandwich estimator to a resampling variance approach for both settings. Finally, we further compare these 2 variance estimation approaches in data examples from the Women's Health Initiative (1993-2005) and the Hispanic Community Health Study/Study of Latinos (2008-2011). In our simulations, the sandwich variance estimator typically had good numerical performance, but simple Wald bootstrap confidence intervals were unstable or overcovered in certain settings, particularly when there was high correlation between covariates or large measurement error.
Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; ...familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.
•GATA2 deficiency has a broad phenotype encompassing immunodeficiency, MDS/AML, pulmonary disease, and vascular/lymphatic dysfunction.•Early genetic diagnosis is critical to direct clinical management, prophylaxis, transplantation, and family screening.
Natural climate solutions are not enough Anderson, Christa M; DeFries, Ruth S; Litterman, Robert ...
Science (American Association for the Advancement of Science),
03/2019, Letnik:
363, Številka:
6430
Journal Article
Recenzirano
Decarbonizing the economy must remain a critical priority
Stabilizing Earth's climate and limiting temperature increase to well below 2°C per the Paris Agreement requires a dramatic uptick in the ...rate of progress on reducing greenhouse gas (GHG) emissions. Natural climate solutions (NCS) can be a substantial contributor, while also providing valuable cobenefits for people and ecosystems. Although analyses of NCS have some differences in the GHG fluxes they consider, all include emissions sources (such as deforestation, land-use change, and agricultural practices), emissions sinks (such as reforestation and restoring degraded lands), and non–carbon dioxide (CO
2
) agricultural emissions (such as methane from livestock). Some of us have contributed to among the most optimistic assessments of the potential of NCS (
1
), whereas others have been more pessimistic (
2
,
3
). But one thing on which we agree, and which technical literature generally acknowledges, is that the benefits of NCS do not decrease the imperative for mitigation from the energy and industrial sectors (
2
,
4
,
5
). Yet this point sometimes gets lost in public-facing conversations for example, are forests “our best weapon for fighting carbon emissions” or, more realistically, just one “piece of the puzzle”? (
6
). Strategies for incorporating NCS with energy and industrial mitigation in the climate portfolio should not be “either/or” but “yes, and.”
Parenting is a critical mediator of children's school readiness. In line with this theory of change, data from the randomized clinical trial of Smart Beginnings (tiered Video Interaction Project and ...Family Check‐Up; N = 403, treatment arm n = 201) were used to examine treatment impacts on early language and literacy skills at child age 4 years (nLatinx = 168, nBlack = 198, nMale = 203), as well as indirect impacts through parental support of cognitive stimulation at child age 2 years. Although results did not reveal direct effects on children's early skills, there were significant indirect effects for early literacy (β = .03, p = .05) and early language (β = .04, p = .04) via improvements in parental cognitive stimulation. Implications for interventions targeting parenting to improve children's school readiness beginning at birth are discussed.
The first table in many articles reporting results of a randomized clinical trial compares baseline factors across arms. Results that appear inconsistent with chance trigger suspicion, and in one ...case, accusation and confirmation of data falsification. We confirm theoretically results of simulation analyses showing that inconsistency with chance is extremely difficult to prove in the absence of any information about correlations between baseline covariates. We offer a reasonable diagnostic to trigger further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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