Small domain estimation of census coverage: A case study in Bayesian analysis of complex survey data

Many countries conduct a full census survey to report official population statistics. As no census survey ever achieves 100 per cent response rate, a post-enumeration survey (PES) is usually conducted and analysed to assess census coverage and produce official population estimates by geographic area and demographic attributes. Considering the usually small size of PES, direct estimation at the desired level of disaggregation is not feasible. Design-based estimation with sampling weight adjustment is a commonly used method but is difficult to implement when survey non-response patterns cannot be fully documented and population benchmarks are not available. We overcome these limitations with a fully model-based Bayesian approach applied to the New Zealand PES. Although theory for the Bayesian treatment of complex surveys has been described, published applications of individual level Bayesian models for complex survey data remain scarce. We provide such an application through a case study of the 2018 census and PES surveys. We implement a multilevel model that accounts for the complex design of PES. We then illustrate how mixed posterior predictive checking and cross-validation can assist with model building and model selection. Finally, we discuss potential methodological improvements to the model and potential solutions to mitigate dependence between the two surveys.Comment: 35 pages, 5 figures This is an author version of a paper accepted for publication in the Journal of Official Statistics. Once published by the Journal of Official Statistics use the Journal citation. This version includes supplementary material and corrected version of Figure

Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers

Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational patterns in human cancers are attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. In this study, we prospectively examine genome-wide aberrations by expressing human APOBEC3A in avian DT40 cells. From whole-genome sequencing, we detect hundreds to thousands of base substitutions per genome. The APOBEC3A signature includes widespread cytidine mutations and a unique insertion-deletion (indel) signature consisting largely of cytidine deletions. This multi-dimensional APOBEC3A signature is prevalent in human cancer genomes. Our data further reveal replication-associated mutations, the rate of stem-loop and clustered mutations, and deamination of methylated cytidines. This comprehensive signature of APOBEC3A mutagenesis is a tool for future studies and a potential biomarker for APOBEC3 activity in cancer

Body Composition Estimation in Youth Athletes: Agreement Between Two-Component Methods

Body composition techniques such as skinfold measurements, air displacement plethysmography, and underwater weighing are commonly performed in athletic populations, particularly in youth athletes who may not have access to other laboratory methods. However, little is known whether such body composition estimates can be directly compared across techniques. PURPOSE: To determine the agreement between common two-component (2C) body composition techniques. METHODS: 90 youth athletes (Males: 39; Females: 51; Age: 18.2 ± 2.4 years; Height: 172.0 ± 9.9 cm; Body Mass: 69.0 ± 12.5 kg; Underwater Weighing [UWW] Body Fat Percentage [%BF]: 20.2 ± 7.0%) participated in this study. 2C estimates of %BF were determined via UWW, air displacement plethysmography (ADP), and 7-site skinfold (SKF) using the applicable Jackson-Pollock equation. Body mass was measured via calibrated scale. Agreement between methods was quantified using Lin’s concordance correlation coefficients (CCC). Estimates of body fat percentage were also compared between techniques using paired samples t-tests (α \u3c 0.05) and equivalence testing, with the threshold of equivalence set at ± 2% body fat. RESULTS: Mean ± SD %BF estimates were 20.2 ± 7.0% (UWW), 18.7 ± 7.3% (ADP), and 16.1 ± 7.2% (SKF). Mean differences between methods were 1.6% [95% CI: 0.8, 2.3] for UWW vs. ADP, 4.1% [95% CI: 3.4, 4.8] for UWW vs. SKF, and 2.6% [95% CI: 1.9, 3.2] for ADP vs. SKF. Paired-samples t-tests revealed significant differences between %BF estimates for each comparison. Likewise, no methods were found to be equivalent, based on a ± 2% BF equivalence range. CCC values were 0.855 for UWW vs. ADP, 0.759 for UWW vs. SKF, and 0.844 for ADP vs. SKF. CONCLUSION: This study suggests limited agreement between 2C %BF estimates derived from three common assessment techniques. Hypothesis testing revealed significant differences between methods, and the magnitude of these differences resulted in non-equivalence at ± 2% BF. Based on these results, it appears that direct comparisons between 2C %BF estimates from these different techniques should be avoided if possible. Though the magnitude of the differences between techniques may be acceptable in certain contexts, coaches and clinicians should strive to utilize the same assessment methodology when examining and comparing body composition results across time

Assessment of Youth Athlete Body Composition using Bioimpedance Techniques as Compared to a Three-Compartment Model

Body composition is believed to contribute to success in many sports. For this reason, assessment of body composition with various devices is commonly performed. The agreement between devices warrants exploration, particularly in groups with limited data, such as youth athletes. PURPOSE: To determine the agreement between a 3-compartment model (3C) and bioelectrical impedance analysis (BIA) devices for assessing body composition in youth athletes. METHODS: The body composition of 90 youth athletes was evaluated (51 F, 39 M; age: 18.2±2.4 y; body mass: 69.0±12.5 kg; height: 172.0±9.9 cm; BMI: 23.2±3.2 kg/m2, BF%: 19.7±6.9%). 3C values were produced using body volume from an underwater weighing system, body water from bioimpedance spectroscopy (ImpediMed SFB7), and body mass from a calibrated scale. Additionally, three BIA techniques were performed: a consumer-grade standing hand-to-foot analyzer (InBody H2ON; BIAINBODY), a consumer-grade standing foot-to-foot analyzer (Tanita BF-680W; BIATANITA), and a laboratory-grade supine hand-to-foot analyzer (RJL Quantum IV; BIARJL). Bioimpedance from BIARJL was inserted into the Matias FFM equation for athletes. BIA BF% and FFM values were compared to 3C values using paired t-tests, Pearson correlations, and the standard error of the estimate (SEE). RESULTS: 3C BF% estimates did not differ from BIAINBODY (-0.9%, 95% CI: -2.1, 0.2) or BIARJL (0.2%, 95% CI: -0.8, 1.2%). However, BF% was underestimated by BIATANITA relative to 3C (-2.7%, 95% CI: -4.1, -1.2). All BIA BF% estimates were significantly correlated with 3C (r: 0.59 to 0.73; R2: 0.35 to 0.53, pINBODY (0.8 kg, 95% CI: -0.1, 1.6) or BIARJL (0.1 kg, 95% CI: -0.6, 0.9). However, FFM was overestimated by BIATANITA relative to 3C (1.8 kg, 95% CI: 0.7, 2.8). All BIA FFM estimates were significantly correlated with 3C (r: 0.92 to 0.97; R2: 0.85 to 0.93, pCONCLUSION: This study demonstrated potentially acceptable agreement between 3C BF% and FFM estimates and those from BIAINBODY and BIARJL, with the athlete-specific equation used with BIARJL demonstrating the best performance. In contrast, the consumer-grade foot-to-foot analyzer underestimated BF% and overestimated FFM. These findings may help inform practical and accurate body composition estimation in youth athletes

MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks

BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient\u27s peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair

Antigen glycosylation regulates efficacy of CAR T cells targeting CD19

While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

Processes and factors involved in decisions regarding return of incidental genomic findings in research

Purpose: Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions—the processes and factors involved—has remained largely unexplored. Methods: We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings. Results: Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants’ well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community-wide genetics education. Conclusion: These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues

Development of an amplicon-based sequencing approach in response to the global emergence of mpox

The 2022 multicountry mpox outbreak concurrent with the ongoing Coronavirus Disease 2019 (COVID-19) pandemic further highlighted the need for genomic surveillance and rapid pathogen whole-genome sequencing. While metagenomic sequencing approaches have been used to sequence many of the early mpox infections, these methods are resource intensive and require samples with high viral DNA concentrations. Given the atypical clinical presentation of cases associated with the outbreak and uncertainty regarding viral load across both the course of infection and anatomical body sites, there was an urgent need for a more sensitive and broadly applicable sequencing approach. Highly multiplexed amplicon-based sequencing (PrimalSeq) was initially developed for sequencing of Zika virus, and later adapted as the main sequencing approach for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we used PrimalScheme to develop a primer scheme for human monkeypox virus that can be used with many sequencing and bioinformatics pipelines implemented in public health laboratories during the COVID-19 pandemic. We sequenced clinical specimens that tested presumptively positive for human monkeypox virus with amplicon-based and metagenomic sequencing approaches. We found notably higher genome coverage across the virus genome, with minimal amplicon drop-outs, in using the amplicon-based sequencing approach, particularly in higher PCR cycle threshold (Ct) (lower DNA titer) samples. Further testing demonstrated that Ct value correlated with the number of sequencing reads and influenced the percent genome coverage. To maximize genome coverage when resources are limited, we recommend selecting samples with a PCR Ct below 31 Ct and generating 1 million sequencing reads per sample. To support national and international public health genomic surveillance efforts, we sent out primer pool aliquots to 10 laboratories across the United States, United Kingdom, Brazil, and Portugal. These public health laboratories successfully implemented the human monkeypox virus primer scheme in various amplicon sequencing workflows and with different sample types across a range of Ct values. Thus, we show that amplicon-based sequencing can provide a rapidly deployable, cost-effective, and flexible approach to pathogen whole-genome sequencing in response to newly emerging pathogens. Importantly, through the implementation of our primer scheme into existing SARS-CoV-2 workflows and across a range of sample types and sequencing platforms, we further demonstrate the potential of this approach for rapid outbreak response.This publication was made possible by CTSA Grant Number UL1 TR001863 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH) awarded to CBFV. INSA was partially funded by the HERA project (Grant/ 2021/PHF/23776) supported by the European Commission through the European Centre for Disease Control (to VB).info:eu-repo/semantics/publishedVersio

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies