Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial.

BACKGROUND: Immunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons. OBJECTIVE: To evaluate antinucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection. DESIGN: Nested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427). SETTING: 99 sites in the United States, July 2020 through March 2021. PARTICIPANTS: Participants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase. INTERVENTION: 2 mRNA-1273 or placebo injections 28 days apart. MEASUREMENTS: Nasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay. RESULTS: Among 812 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% [95% CI, 27% to 54%]) versus 605 of 648 placebo recipients (93% [CI, 92% to 95%]). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 [CI, 1.59 to 2.28]). LIMITATION: The scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial. CONCLUSION: Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Stopping Trials Early Due to Harm.

Stopping Trials Early Due to HarmDSMBs protect clinical trial participants from harm. We describe two trials stopped for potential harm to enrollees: a DSMB recommended termination soon after enrollment began when data showed higher mortality in the experimental versus the control arm, and a trial with completed enrollment was stopped while participants were being followed and treated.

Modeling repeated labor curves in consecutive pregnancies: Individualized prediction of labor progression from previous pregnancy data.

The measurement of cervical dilation of a pregnant woman is used to monitor the progression of labor until 10 cm when pushing begins. There is anecdotal evidence that labor tracks across repeated pregnancies; moreover, no statistical methodology has been developed to address this important issue, which can help obstetricians make more informed clinical decisions about an individual woman's progression. Motivated by the NICHD Consecutive Pregnancies Study (CPS), we propose new methodology for analyzing labor curves across consecutive pregnancies. Our focus is both on studying the correlation between repeated labor curves on the same woman and on using the cervical dilation data from prior pregnancies to predict subsequent labor curves. We propose a hierarchical random effects model with a random change point that characterizes repeated labor curves within and between women to address these issues. We employ Bayesian methodology for parameter estimation and prediction. Model diagnostics to examine the appropriateness of the hierarchical random effects structure for characterizing the dependence structure across consecutive pregnancies are also proposed. The methodology was used in analyzing the CPS data and in developing a predictor for labor progression that can be used in clinical practice.

A Joint Model Approach for Longitudinal Data with no Time-Zero and Time-To-Event with Competing Risks.

The joint modeling of longitudinal and time-to-event data is an active area in biostatistics research. The focus of this article is on developing a modeling framework for these joint models when the longitudinal and time-to-event data do not have a meaningful time-zero. The motivating example is the study of a longitudinal assessment of station during child labor and it's relationship to time-to-delivery. A good predictor of delivery type and timing would help obstetricians better manage the end of pregnancy and better facilitate delivery. One measure of labor progression is station, a measure of the position of the fetus' head in relation to the pelvis of the pregnant women, may be a good marker for delivery time and type. However, women enter the hospital, where their station is closely monitored, at arbitrary points in their labor process, resulting in no clear time zero. In addition, since delivery may be of various types, the competing risks due to type need to be accounted for. We develop a joint model of longitudinal and time-to-event data for this situation. The model is formulated through shared random effects between the survival and longitudinal processes, and parameter estimation is conducted through a Bayesian approach. The model is illustrated with longitudinal data on station where the relationship between station and event-time is studied and the model is used to assess the ability of longitudinal measures of station to predict the type and timing of pregnancy. We illustrate the methodology with longitudinal data taken during labor.

A thrifty variant in CREBRF strongly influences body mass index in Samoans.

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity.

Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale.

BACKGROUND: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples. METHODS: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were, respectively, employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test. RESULTS: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After "removing" batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects. CONCLUSION: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects.

Additive effect of age on disability for individuals with spinal cord injuries.

OBJECTIVE: To examine the additive effect of age on disability for adults with spinal cord injury (SCI). DESIGN: Prospective cohort study. SETTING: SCI Model Systems. PARTICIPANTS: Individuals with SCI (median age at injury, 32 y; range, 6-88 y) with a discharge motor FIM score and at least 1 follow-up motor FIM score who also provided measures of other covariates (N=1660). Of the total sample, 79% were men, 72% were white, 16% had incomplete paraplegia, 33% had complete paraplegia, 30% had incomplete tetraplegia, and 21% had complete tetraplegia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary study outcome was the motor subscale of the FIM. A mixed-models approach was used to examine the additive effect of age on disability for individuals with SCI. RESULTS: When controlling for motor FIM at discharge from rehabilitation, level and severity of injury, age at injury, sex, race, and the age × time interaction were not significant (P=.07). Age at the time of SCI was significantly associated with motor FIM (F1,238=22.49, P<.001). Two sensitivity analyses found significant interactions for both age × time (P=.03, P=.02) and age × time-square (P=.01, P=.006) models. Trajectory of motor FIM scores is moderated slightly by age at the time of injury. The older participants were at the time of injury, the greater the curvature and the more rapid decline were found in later years. CONCLUSIONS: These findings indicate that age moderately influences disability for some individuals with SCI: the older the age at the time of injury, the greater the influence age has on disability. The findings serve as an important empirical foundation for the evaluation and development of interventions designed to augment accelerated aging experienced by individuals with SCI.