Covariate handling approaches in combination with dynamic borrowing for hybrid control studies.

Borrowing data from external control has been an appealing strategy for evidence synthesis when conducting randomized controlled trials (RCTs). Often named hybrid control trials, they leverage existing control data from clinical trials or potentially real-world data (RWD), enable trial designs to allocate more patients to the novel intervention arm, and improve the efficiency or lower the cost of the primary RCT. Several methods have been established and developed to borrow external control data, among which the propensity score methods and Bayesian dynamic borrowing framework play essential roles. Noticing the unique strengths of propensity score methods and Bayesian hierarchical models, we utilize both methods in a complementary manner to analyze hybrid control studies. In this article, we review methods including covariate adjustments, propensity score matching and weighting in combination with dynamic borrowing and compare the performance of these methods through comprehensive simulations. Different degrees of covariate imbalance and confounding are examined. Our findings suggested that the conventional covariate adjustment in combination with the Bayesian commensurate prior model provides the highest power with good type I error control under the investigated settings. It has desired performance especially under scenarios of different degrees of confounding. To estimate efficacy signals in the exploratory setting, the covariate adjustment method in combination with the Bayesian commensurate prior is recommended.

Evaluating Pediatric Families' Understanding of and Reactions to COVID-19 Visitor Restrictions.

The COVID-19 pandemic led to changes in hospital visitor policies and little is known about the impact on patients and their families. This study evaluated families' understanding of and reactions to COVID-19-related visitor restriction policy at an academic children's hospital. We conducted a cross-sectional study with families of patients admitted to the pediatric ICU and general pediatric wards from September 2020 to November 2020. Parents (n = 73) completed a survey assessing communication, understanding of and satisfaction with visitor policies, strategies of coping with illness, and Hospital Anxiety and Depression Scale (HADS) scores. Descriptive analyses were performed to summarize data. Associations between outcomes and participant characteristics were examined. A majority (88%) of respondents reported hospital visitor restrictions were explained, usually in-person (94%), and understood the policy "very well" (68%), but none correctly identified all reasons for visitation restrictions. Eighty-five percent reported other family/friends would have visited, however minority families were more likely to report they would have had fewer visitors if restrictions were not in place (P = 0.0385). A majority (69%) were satisfied with how the hospital handled visitor polices, and parents of older children were more satisfied (P < .0001). HADS scores were consistent with anxiety or depression in about half of respondents. Forty percent of respondents believed restrictions affected their own and their child's ability to cope during hospitalization. Parents expressed satisfaction with and understanding of visitor policies but did not understand the rationale for visitor restrictions. Visitor restrictions may impact parental and child coping and mental health outcomes.

SNP-SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children.

We studied associations of persistent respiratory morbidity (PRM) at 6 and 12 months after acute respiratory failure (ARF) in previously healthy children with single-nucleotide polymorphisms (SNPs) of surfactant protein (SP) genes. Of the 250 enrolled subjects, 155 and 127 were followed at 6 and 12 months after an ARF episode, respectively. Logistic regression analysis and SNP-SNP interaction models were used. We found that 1) in the multivariate analysis, an increased risk at 6 and 12 months was associated with rs1124_A and rs4715_A of SFTPC, respectively; 2) in a single SNP model, increased and decreased risks of PRM at both timepoints were associated with rs1124 of SFTPC and rs721917 of SFTPD, respectively; an increased risk at 6 months was associated with rs1130866 of SFTPB and rs4715 of SFTPC, and increased and decreased risks at 12 months were associated with rs17886395 of SFTPA2 and rs2243639 of SFTPD, respectively; 3) in a two-SNP model, PRM susceptibility at both timepoints was associated with a number of intergenic interactions between SNPs of the studied SP genes. An increased risk at 12 months was associated with one intragenic (rs1965708 and rs113645 of SFTPA2) interaction; 4) in a three-SNP model, decreased and increased risks at 6 and 12 months, respectively, were associated with an interaction among rs1130866 of SFTPB, rs721917 of SFTPD, and rs1059046 of SFTPA2. A decreased risk at 6 months was associated with an interaction among the same SNPs of SFTPB and SFTPD and the rs1136450 of SFTPA1. The findings revealed that SNPs of all SFTPs appear to play a role in long-term outcomes of ARF survivors and may serve as markers for disease susceptibility.

Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis.

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was 67% (95% Bayesian credible interval [CrI], 53-77%) and 31% (95% CrI, 18-44%), respectively. Achievement of an MRD-negative response was associated with superior DFS and OS, regardless of MRD threshold or analytic sensitivity. Among patients in CR, the benefit of MRD negativity was highest in studies using an MRD cutoff less than 0.1%. The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

Comprehensive investigations of mixed convection of Fe-ethylene-glycol nanofluid inside an enclosure with different obstacles using lattice Boltzmann method.

In the present paper, nanofluid mixed convection is investigated in a square cavity with an adiabatic obstacle by using the Lattice Boltzmann method (LBM). This enclosure contains Fe-ethylene-glycol nanofluid and three constant temperature thermal sources at the left wall and bottom of the enclosure through a lateral wall. The fluid is incompressible, laminar, and Newtonian. The obtained results are presented in the constant Ra = 104 and a Pr = 0.71 for different Ri = 0.1, 1, and 10. The effects of the slope of the enclosure, volume fraction of nanoparticles [Formula: see text], the location of adiabatic obstacles, and nanoparticle diameter in the fluid are investigated on the value of heat transfer. A change in the attack angle of the enclosure leads to changes in the movement distance for fluid between hot and cold sources and passing fluid through case E, which affects the flow pattern strongly. In each attack angle, on colliding with an obstacle, the fluid heat transfers between two sources, which leads to uniform heat transfer in the enclosure. By increasing the velocity of the lid, the Richardson number decreases leading to improvement of the convective heat transfer coefficient and Nusselt number enhancement. The results so obtained reveal that by augmenting [Formula: see text] value the effect of Richardson number reduction can augment Nusselt number and the amount of absorbed heat from the hot surface. Consequently, in each state where a better flow mixture and lower depreciation of fluid velocity components, due to the penetration of lid movement and buoyancy force, occurs higher heat transfer rate is accomplished. Furthermore, it is shown that when Ri = 0.1, the effect of cavity angle is more important but when Ri = 10, the effect of the position of obstacle is more visible.

Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.

IMPORTANCE: Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points. OBJECTIVE: To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature. DATA SOURCES: Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE. STUDY SELECTION: Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non-English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded. DATA EXTRACTION AND SYNTHESIS: Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling. MAIN OUTCOMES AND MEASURES: Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status. RESULTS: Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization. CONCLUSIONS AND RELEVANCE: The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.

SNP and Haplotype Interaction Models Reveal Association of Surfactant Protein Gene Polymorphisms With Hypersensitivity Pneumonitis of Mexican Population.

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by inhalation of common environmental organic particles. Surfactant proteins (SPs) play a role in innate immunity and surfactant function. We hypothesized that single nucleotide polymorphisms (SNPs) or haplotypes of the SP genes associate with HP. Methods: Seventy-five HP patients caused by avian antigen and 258 controls, asymptomatic antigen exposed and non-exposed were enrolled. SNP association was performed using logistic regression analysis and SNP-SNP interaction models. Results: Based on odds ratio, regression analyses showed association of (a) rs7316_G, 1A3 (protective) compared to antigen exposed; (b) male sex, smoking, rs721917_T and rs1130866_T (protective) compared to non-exposed controls with HP; (c) compared to antigen exposed, 25 interactions associated with HP in a three-SNP model; (d) compared to non-exposed, (i) rs1136451 associated with increased, whereas rs1136450 and rs1130866 associated with lower HP risk, (ii) 97 interactions associated with HP in a three-SNP model. The majority of SNP-SNP interactions associated with increased HP risk involved SNPs of the hydrophilic SPs, whereas, the majority of interactions associated with lower HP risk involved SNPs of both hydrophilic and hydrophobic SPs; (e) haplotypes of SP genes associated with HP risk. Conclusions: The complexity of SNPs interactions of the SFTP genes observed indicate that the lung inflammatory response to avian antigens is modulated by a complex gene interplay rather than by single SNPs.