Repeated low‐dose challenge studies provide valuable information when evaluating candidate vaccines since they resemble the typical exposure of natural transmission and inform on the number of ...exposures prior to infection. Traditionally, the number of challenges to infection has been used as the outcome. This work uses the number of infecting viruses, or founder viruses at the time of infection, to more efficiently characterize a vaccine's mechanism of action. The vaccine mechanisms of action we consider are a Null mechanism (the vaccine offers no protection), a Leaky mechanism in which the number of founder viruses is reduced by some factor in vaccinated subjects, the All‐or‐None mechanism in which the vaccine randomly provides either complete protection or no protection in vaccinated subjects, and a Combination mechanism with both Leaky and All‐or‐None components. We consider two discrete marked survival models where the number of founder viruses follows a Poisson distribution with either a fixed mean parameter (Poisson model), or a random mean parameter that follows a Gamma distribution (negative binomial model). We estimate the models using maximum likelihood and derive likelihood ratio testing procedures that are accurate for small samples with boundary parameters. We illustrate the performance of these methodologies with a data example of simian immunodeficiency virus on nonhuman primates and a simulation study.
Accurate assessment of gestational age at birth is necessary for optimal pediatric care. In high resource countries, several methods using ultrasound have been proposed to assess gestational age at ...birth; however, these methods are not easily accessible for low‐resource populations. We develop a shared random parameter model for estimating gestational age at birth from longitudinal maternal anthropometry that incorporates additional maternal information from the last menstrual period, a measure of gestational age collected with sizable measurement error. The proposed methodology is evaluated using simulation studies under a training‐test set paradigm. In addition, we propose methodology to validate prediction when some measurements of the gold standard are collected with measurement error. We illustrate the proposed methodologies with data from the NICHD Fetal Growth Studies.
Abstract
Background
The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood.
Methods
Data of 74 patients with anti-IFN-γ ...autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples.
Results
Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001).
Conclusions
Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.
Patients with anti-interferon-γ autoantibodies in Thailand and the United States had distinct clinical features. While titers decreased with time, 24% of Thai patients died during 7.5 years of follow-up. None of the US patients died during a median follow-up period of 4.5 years.
Designing clinical trials for emerging infectious diseases such as COVID-19 is challenging because information needed for proper planning may be lacking. Pre-specified adaptive designs can be ...attractive options, but what happens if a trial with no such design needs to be modified? For example, unexpectedly high efficacy (approximately 95%) in two COVID-19 vaccine trials might cause investigators in other COVID-19 vaccine trials to increase the number of interim analyses to allow earlier stopping for efficacy. If such a decision is based solely on external data, there are no issues, but what if internal trial data by arm are also examined? Fortunately, the conditional error principle of Müller and Schäfer (2004) can be used to ensure no inflation of the type 1 error rate, even if no interim analyses were planned. We study the properties, including limitations, of this method. We provide a shiny app to evaluate changes in timing of interim analyses in response to outcome data by arm in clinical trials.
In matched case-crossover studies, any stratum effect is removed by conditioning on the fixed number of case–control sets in the stratum, and hence, the conditional logistic regression model is not ...able to detect any effects associated with matching covariates. However, some matching covariates such as time and location often modify the effect of covariates, making the estimations obtained by conditional logistic regression incorrect. Therefore, in this paper, we propose a flexible derivative time-varying coefficient model to evaluate effect modification by time and location, in order to make correct statistical inference, when the number of locations is small. Our proposed model is developed under the Bayesian hierarchical model framework and allows us to simultaneously detect relationships between the predictor and binary outcome and between the predictor and time. Inference is proposed based on the derivative function of the estimated function to determine whether there is an effect modification due to time and/or location, for a small number of locations among the participants. We demonstrate the accuracy of the estimation using a simulation study and an epidemiological example of a 1–4 bidirectional case-crossover study of childhood aseptic meningitis with drinking water turbidity.
People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping ...clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity.
HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points.
HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients.
Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS FIRIS). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.
Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of ...immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations.
We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality.
After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval CI, 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher.
Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).
In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency ...virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen.
The gut microbiome is plausibly associated with colorectal cancer risk; however, previous studies mostly investigated this association cross-sectionally. We investigated cross-sectional and ...prospective associations of the rectal tissue microbiome with adenoma recurrence in the Polyp Prevention Trial (PPT).
PPT is a 4-year randomized clinical trial of the effect of a dietary intervention on adenoma recurrence among community members. We extracted DNA from rectal biopsies at baseline, end of year 1, and end of year 4 among 455 individuals and sequenced the V4 region of the 16S rRNA gene. At each timepoint, we investigated associations of alpha diversity, beta diversity, and presence and relative abundance of select taxa with adenoma recurrence using multivariable logistic regression.
Variation in beta diversity was primarily explained by subject and minimally by year of collection or time between biopsy and colonoscopy. Cross-sectionally, year 4 alpha diversity was strongly, inversely associated with adenoma prevalence ORQ3 vs. Q1 Shannon index = 0.40 (95% confidence interval, CI: 0.21-0.76). Prospective alpha diversity associations (i.e., baseline/year 1 alpha diversity with adenoma recurrence 3-4 years later) were weak or null, as were cross-sectional and prospective beta diversity-adenoma associations. Bacteroides abundance was more strongly, positively associated with adenoma prevalence cross-sectionally than prospectively.
Rectal tissue microbiome profiles may be associated with prevalent adenomas, with little evidence supporting prospective associations.
Additional prospective studies, with serial fecal and tissue samples, to explore microbiome-colorectal cancer associations are needed. Eventually, it may be possible to use microbiome characteristics as intervenable risk factors or screening tools.
PDF
