Nevin Manimala

Biometrics. 2022 Jun 28. doi: 10.1111/biom.13710. Online ahead of print.

ABSTRACT

Randomized clinical trials with time-to-event endpoints are frequently stopped after a pre-specified number of events has been observed. This practice leads to dependent data and non-random censoring, which can in general not be solved by conditioning on the underlying baseline information. In case of staggered study entry, matters are complicated substantially. The present paper demonstrates that the study design at hand entails general independent censoring in the counting process sense, provided that the analysis is based on study time information only. To illustrate that the filtrations must not use abundant information, we simulated data of event-driven trials and evaluated them by means of Cox regression models with covariates for the calendar times. The Breslow curves of the cumulative baseline hazard showed considerable deviations, which implies that the analysis is disturbed by conditioning on the calendar time variables. A second simulation study further revealed that Efron’s classical bootstrap, unlike the (martingale-based) wild bootstrap, may lead to biased results in the given setting, as the assumption of random censoring is violated. This is exemplified by an analysis of data on immunotherapy in patients with advanced, previously treated non-small cell lung cancer.

PMID:35762259 | DOI:10.1111/biom.13710

Indoor Air. 2022 Jun;32(6):e13065. doi: 10.1111/ina.13065.

ABSTRACT

Heating and cooling requirement differences across climates not only have carbon emissions and energy efficiency implications but also impact indoor air quality (IAQ) and health. Energy and IAQ building simulation models help understand tradeoffs or co-benefits, but these have not been applied to evaluate climate zone or multi-family home differences. We modeled a four-story multi-family home in six U.S. climate zones and quantified energy, IAQ, and health outcomes with EnergyPlus, CONTAM, and a pediatric asthma systems science model. Pollutant sources included cooking and ambient. Outputs were daily PM_2.5 and NO₂ indoor concentrations, infiltration, energy for heating and cooling, and asthma exacerbations, which were compared across climate zones, apartment units, and resident behaviors. Daily ambient-sourced PM_2.5 decreased and cooking-sourced PM_2.5 increased with higher ambient temperatures. Infiltration air changes per hour were higher on the first versus the fourth floor and in colder climates. Window opening during cooking led to decreases in total pollutant concentrations (11%-18% for PM_2.5 and 9%-15% for NO₂ ), 3%-4% decreases in asthma exacerbations within climate zones, and minimal impacts on cooling, but led to increased heating demand (4%-8%). Our results demonstrate the influence of meteorology, multi-family building characteristics, and resident behavior on IAQ, energy, and health, focused on multi-zone methodology.

PMID:35762242 | DOI:10.1111/ina.13065

Indoor Air. 2022 Jun;32(6):e13069. doi: 10.1111/ina.13069.

ABSTRACT

Secondhand smoke (SHS) remains a common health threat in densely populated, urban settings. We estimated the prevalence of exposure and associated respiratory symptoms, knowledge, attitudes, and behaviors in a multi-ethnic, weighted sample of Singapore residents using a cross-sectional survey of 1806 adults. We weighted data to match the national population in terms of gender, ethnicity, and education level and analyzed data using descriptive statistics, bivariate analyses, multiple linear and logistic regressions, and a multinomial logistic regression model. About 88% of respondents reported regular SHS exposure. Nearly 57% reported exposure to neighbors’ SHS at home. Respiratory symptoms were reported by 32.5% and significantly associated with exposure to daily (AOR = 2.63, 95% CI = 1.62-4.36), non-daily (AOR = 1.75, 95% CI = 1.14-2.77), and neighbors’ (AOR = 1.37, 95% CI = 1.07-1.76) SHS. More knowledge of SHS was associated with male gender (β = 0.28, p = 0.0009) and higher household income (linear trend; p = 0.0400). More negative attitudes to SHS were associated with older age (linear trend; p < 0.0001). Engaging in behaviors to avoid SHS was associated with a more negative attitude to SHS (AOR = 1.09-1.23). SHS exposure is common in Singapore’s densely populated setting and associated with respiratory symptoms, even if exposure is non-daily or from neighboring homes.

PMID:35762238 | DOI:10.1111/ina.13069

Indoor Air. 2022 Jun;32(6):e13055. doi: 10.1111/ina.13055.

ABSTRACT

Environmental carbon dioxide (CO₂ ) could affect various mental and physiological activities in humans, but its effect on daytime sleepiness is still controversial. In a randomized and counterbalanced crossover study with twelve healthy volunteers, we applied a combinational approach using classical frequentist and Bayesian statistics to analyze the CO₂ exposure effect on daytime sleepiness and electroencephalogram (EEG) signals. Subjective sleepiness was measured by the Japanese Karolinska Sleepiness Scale (KSS-J) by recording EEG during CO₂ exposure at different concentrations: Normal (C), 4000 ppm (Moderately High: MH), and 40 000 ppm (high: H). The daytime sleepiness was significantly affected by the exposure time but not the CO₂ condition in the classical statistics. On the other hand, the Bayesian paired t-test revealed that the CO₂ exposure at the MH condition might induce daytime sleepiness at the 40-min point compared with the C condition. By contrast, EEG was significantly affected by a short exposure to the H condition but not exposure time. The Bayesian analysis of EEG was primarily consistent with results by the classical statistics but showed different credible levels in the Bayes’ factor. Our result suggested that the EEG may not be suitable to detect objective sleepiness induced by CO₂ exposure because the EEG signal was highly sensitive to environmental CO₂ concentration. Our study would be helpful for researchers to revisit whether EEG is applicable as a judgment indicator of objective sleepiness.

PMID:35762237 | DOI:10.1111/ina.13055

Pharm Stat. 2022 Jun 28. doi: 10.1002/pst.2244. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has affected clinical trials across disease areas, raising the questions how interpretable results can be obtained from impacted studies. Applying the estimands framework, analyses may seek to estimate the treatment effect in the hypothetical absence of such impact. However, no established estimators exist. This simulation study, based on an ongoing clinical trial in patients with Tourette syndrome, compares the performance of candidate estimators for estimands including either a continuous or binary variable and applying a hypothetical strategy for COVID-19-related intercurrent events (IE). The performance is investigated in a wide range of scenarios, under the null and the alternative hypotheses, including different modeling assumptions for the effect of the IE and proportions of affected patients ranging from 10% to 80%. Bias and type I error inflation were minimal or absent for most estimators under most scenarios, with only multiple imputation- and weighting-based methods displaying a type I error inflation in some scenarios. Of more concern, all methods that discarded post-IE data displayed a sharp decrease of power proportional to the proportion of affected patients, corresponding to both a reduced precision of estimation and larger confidence intervals. The simulation study shows that de-mediation via g-estimation is a promising approach. Besides showing the best performance in our simulation study, these approaches allow to estimate the effect of the IE on the outcome and cross-compare between different studies affected by similar IEs. Importantly, the results can be extrapolated to IEs not related to COVID-19 that follow a similar causal structure.

PMID:35762230 | DOI:10.1002/pst.2244

Trials. 2022 Jun 27;23(1):532. doi: 10.1186/s13063-022-06357-y.

ABSTRACT

BACKGROUND: More than a third of the 65,000 people living with kidney failure in the UK attend a dialysis unit 2-5 times a week to have their blood cleaned for 3-5 h. In haemodialysis (HD), toxins are removed by diffusion, which can be enhanced using a high-flux dialyser. This can be augmented with convection, as occurs in haemodiafiltration (HDF), and improved outcomes have been reported in people who are able to achieve high volumes of convection. This study compares the clinical- and cost-effectiveness of high-volume HDF compared with high-flux HD in the treatment of kidney failure.

METHODS: This is a UK-based, multi-centre, non-blinded randomised controlled trial. Adult patients already receiving HD or HDF will be randomised 1:1 to high-volume HDF (aiming for 21+ L of substitution fluid adjusted for body surface area) or high-flux HD. Exclusion criteria include lack of capacity to consent, life expectancy less than 3 months, on HD/HDF for less than 4 weeks, planned living kidney donor transplant or home dialysis scheduled within 3 months, prior intolerance of HDF and not suitable for high-volume HDF for other clinical reasons. The primary outcome is a composite of non-cancer mortality or hospital admission with a cardiovascular event or infection during follow-up (minimum 32 months, maximum 91 months) determined from routine data. Secondary outcomes include all-cause mortality, cardiovascular- and infection-related morbidity and mortality, health-related quality of life, cost-effectiveness and environmental impact. Baseline data will be collected by research personnel on-site. Follow-up data will be collected by linkage to routine healthcare databases – Hospital Episode Statistics, Civil Registration, Public Health England and the UK Renal Registry (UKRR) in England, and equivalent databases in Scotland and Wales, as necessary – and centrally administered patient-completed questionnaires. In addition, research personnel on-site will monitor for adverse events and collect data on adherence to the protocol (monthly during recruitment and quarterly during follow-up).

DISCUSSION: This study will provide evidence of the effectiveness and cost-effectiveness of HD as compared to HDF for adults with kidney failure in-centre HD or HDF. It will inform management for this patient group in the UK and internationally.

TRIAL REGISTRATION: ISRCTN10997319 . Registered on 10 October 2017.

PMID:35761367 | DOI:10.1186/s13063-022-06357-y

Trials. 2022 Jun 27;23(1):535. doi: 10.1186/s13063-022-06481-9.

ABSTRACT

BACKGROUND: Blinding is an established approach in clinical trials which aims to minimise the risk of performance and detection bias. There is little empirical evidence to guide UK clinical trials units (CTUs) about the practice of blinding statisticians. Guidelines recommend that statisticians remain blinded to allocation prior to the final analysis. As these guidelines are not based on empirical evidence, this study undertook a qualitative investigation relating to when and how statisticians should be blinded in clinical trials.

METHODS: Data were collected through online focus groups with various stakeholders who work in the delivery and oversight of clinical trials. Recordings of the focus groups were transcribed verbatim and thematic analysis was used to analyse the transcripts.

RESULTS: Thirty-seven participants from 19 CTUs participated in one of six focus groups. Four main themes were identified, namely statistical models of work, factors affecting the decision to blind statisticians, benefits of blinding/not blinding statisticians and practicalities. Factors influencing the decision to blind the statistician included available resources, study design and types of intervention and outcomes and analysis. Although blinding of the statistician is perceived as a desirable mitigation against bias, there was uncertainty about the extent to which an unblinded statistician might impart bias. Instead, in most cases, the insight that the statistician offers was deemed more important to delivery of a trial than the risk of bias they may introduce if unblinded. Blinding of statisticians was only considered achievable with the appropriate resource and staffing, which were not always available. In many cases, a standard approach to blinding was therefore considered unrealistic and impractical; hence the need for a proportionate risk assessment approach identifying possible mitigations.

CONCLUSIONS: There was wide variation in practice between UK CTUs regarding the blinding of trial statisticians. A risk assessment approach would enable CTUs to identify risks associated with unblinded statisticians conducting the final analysis and alternative mitigation strategies. The findings of this study will be used to design guidance and a tool to support this risk assessment process.

PMID:35761345 | DOI:10.1186/s13063-022-06481-9

Head Face Med. 2022 Jun 27;18(1):19. doi: 10.1186/s13005-022-00325-2.

ABSTRACT

BACKGROUND: The study aims to evaluate the accuracy of the generative adversarial networks (GAN) for reconstructing bony midfacial defects.

METHODS: According to anatomy, the bony midface was divided into five subunit structural regions and artificial defects are manually created on the corresponding CT images. GAN is trained to reconstruct artificial defects to their previous normal shape and tested. The clinical defects are reconstructed by the trained GAN, where the midspan defects were used for qualitative evaluation and the unilateral defects were used for quantitative evaluation. The cosine similarity and the mean error are used to evaluate the accuracy of reconstruction. The Mann-Whitney U test is used to detect whether reconstruction errors were consistent in artificial and unilateral clinical defects.

RESULTS: This study included 518 normal CT data, with 415 in training set and 103 in testing set, and 17 real patient data, with 2 midspan defects and 15 unilateral defects. Reconstruction of midspan clinical defects assessed by experts is acceptable. The cosine similarity in the reconstruction of artificial defects and unilateral clinical defects is 0.97 ± 0.01 and 0.96 ± 0.01, P = 0.695. The mean error in the reconstruction of artificial defects and unilateral clinical defects is 0.59 ± 0.31 mm and 0.48 ± 0.08 mm, P = 0.09.

CONCLUSION: GAN-based virtual reconstruction technology has reached a high accuracy in testing set, and statistical tests suggest that it can achieve similar results in real patient data. This study has preliminarily solved the problem of bony midfacial defect without reference.

PMID:35761334 | DOI:10.1186/s13005-022-00325-2

BMC Res Notes. 2022 Jun 27;15(1):224. doi: 10.1186/s13104-022-06110-3.

ABSTRACT

OBJECTIVE: Since there is no material in the market met all the ideal requirements of an impression material, thus in an attempt to find one, hybridization between the two most commonly used impression materials were done. The aim of the hybridization was to obtain a new material combining the good merits of both and eliminate their shortcomings. Thus, this study aimed to assess the impact of hybridization between polyether with addition silicone on tear strength and elastic recovery of the new material and compare such effect with regard to parent materials.

RESULTS: A polyether (PE), polyvinyl siloxanse (PVS) and vinyl polyether silicone (VPES) hybrid elastomers were used in the present study. Tear strength was measured one hour after setting time of each material according to the manufacturer and the three materials showed statistically comparable tear strength in N/mm. Elastic recovery was evaluated one minute after the setting time recommended by the manufacturer. The three materials were statistically insignificant from each other, and all met the ISO4823 requirement of having greater than 96.5% recovery.

PMID:35761301 | DOI:10.1186/s13104-022-06110-3

Biomed Eng Online. 2022 Jun 27;21(1):42. doi: 10.1186/s12938-022-01011-9.

ABSTRACT

BACKGROUND: It is known that inflammatory bowel disease is the result of a defective immune system, and immunotherapy and biological therapy have gradually become important means to treat it. This paper focused on the bibliometric statistical analysis of the current research progress to summarize the research status of this field and analyze the research trends in recent years.

METHODS: Two visualization tools, CiteSpace and VOSviewer, were used to explore the data of journals, institutions, countries/regions, authors, references, and keywords for the literature included in the Web of Science Core Collection from January 1, 2002, to December 31, 2021.

RESULTS: A total of 312 papers were published in 120 journals by 603 institutions from 40 countries/regions, with 9463 co-cited references. The United States has the most publications with the highest total citations in the world. Inflammatory Bowel Diseases published the maximum number of papers, and Gastroenterology devoted the most co-citations to immunotherapy and biological therapy for IBD. In addition, we found that the studies before 2009 mostly focused on clinical trials while researchers have paid more attention to clinical management in therapy for IBD since 2009. Combination therapy and management of the treatment for the disease have become research hotspots.

CONCLUSION: The focus of immunotherapy and biotherapy for IBD has shifted from clinical trials to the management of the risks and benefits of immunotherapy.

PMID:35761289 | DOI:10.1186/s12938-022-01011-9