Sample Size Considerations Research Articles

A Phase 2 Study of Futibatinib (TAS-120) in Patients with Myeloid or Lymphoid Neoplasms Harboring Fibroblast Growth Factor Receptor (FGFR) 1 Rearrangements

▪Background: Myeloid and lymphoid neoplasms (MLNs) with FGFR1 rearrangements are very rare but aggressive myeloproliferative malignancies, characterized by eosinophilia, lymphoid aggregates, and often myelofibrosis, and are recognized as a distinct disease group by the World Health Organization (WHO). In these neoplasms, FGFR1 rearrangements drive oncogenesis via dysregulation of downstream FGFR signaling. Allogenic hematological stem cell transplant (HSCT) is the recommended treatment for patients with FGFR1-rearranged MLNs, as these malignancies are often refractory to chemotherapy and tyrosine kinase inhibitors. Currently, no effective molecularly targeted treatments are available for these patients. Futibatinib is an oral, highly selective, irreversible inhibitor of FGFR1-4 that has shown antitumor activity against FGFR-deregulated tumors in preclinical experiments and in phase 1 studies. Recent results from a phase 2 study demonstrated the efficacy (42% objective response rate) and manageable safety of futibatinib in patients with FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In addition to cholangiocarcinoma, futibatinib treatment resulted in objective responses across tumor types harboring various FGFR aberrations in the phase 1 study. In a separate report, a patient with an FGFR1-driven myeloid neoplasm treated with futibatinib achieved complete hematologic and cytogenetic remission. Based on these data, a multicohort phase 2 study (NCT04189445) was designed to evaluate the efficacy and safety of futibatinib in patients with tumors harboring specific FGFR aberrations. Here, we describe the cohort of patients with MLNs harboring FGFR1 rearrangements.Study Design and Methods: In this global, open-label, multicohort phase 2 study, patients (≥18 years, with Eastern Cooperative Oncology Group performance status 0-1 and adequate organ function) will be enrolled into 1 of 3 cohorts by type of tumor and/or FGFR aberration. The cohort of patients with MLNs harboring FGFR1 rearrangements (as defined by WHO criteria) will include patients who are not candidates for HSCT or other therapies or who have disease progression following HSCT. Patients with clinically significant alterations in calcium-phosphorus homeostasis, ectopic mineralization/calcification, clinically significant retinal/corneal disorder, untreated or clinically/radiologically unstable brain metastases, or prior FGFR inhibitor treatment will be excluded. Approximately 20 patients will be enrolled in this cohort (sample size considerations based on differentiating a ≤10% historical control complete response [CR] rate with a 50% target CR rate with 95% power). Patients will receive futibatinib 20 mg once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criterion is met. The primary endpoint is CR rate. Secondary endpoints include objective response rate, CR with incomplete hematological recovery (CRi) rate, complete or partial cytogenetic response rate, and safety. Additional secondary endpoints are duration of CR, CR+CRi, and response; as well as event-free (leukemia presentation only), progression-free, relapse-free, and overall survival. The study was initiated in August 2020, and patient enrollment is ongoing. DisclosuresKiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Shitara: Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharm, Astellas Pharm, Medi Science, Eisai, Taiho Oncology: Research Funding; Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Novartis, Abbvie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim: Consultancy; Novartis, Abbvie, Yakult: Other: Speaker fee. Rosen: Taiho Oncology: Research Funding. Rha: Taiho Oncology, Inc.: Research Funding. He: Taiho Oncology, Inc.: Research Funding. Oh: Taiho Oncology, Inc.: Research Funding; AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok: Other: Grants or contracts from any entity; AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point: Other: Participation on a data safety monitoring board or advisory board. Melisi: Taiho Oncology, Inc.: Research Funding. Iwasa: Taiho Oncology, Inc.: Honoraria, Research Funding. Jiang: Taiho Oncology, Inc.: Research Funding. Liu: Taiho Oncology, Inc.: Current Employment. Takahashi: Taiho Oncology, Inc.: Current Employment. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

Helicobacter pylori and Respiratory Diseases: 2021 Update.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

Assessment and novel application ofN‐mixture models for aerial surveys of wildlife

AbstractAerial surveys are a critical tool for inference of wildlife populations, yet are limited by current available methods to account for imperfect detection without marking animals.N‐mixture models use count data from replicate surveys for estimation of wildlife abundance while accounting for imperfect detection. This statistical framework was recently developed but is rarely applied to aerial surveys of terrestrial wildlife. We applied anN‐mixture model incorporating temporary emigration to a novel aerial survey design to estimate the availability, detection probability, and abundance of an unmarked population of white‐tailed deer (Odocoileus virginianus) in Michigan, USA, using surveys in 2014 and 2016. We assessed the selection of the sample unit size for theN‐mixture model in a post hoc sensitivity analysis and compared all estimates to a hierarchical distance sampling (HDS) approach. Hierarchical distance sampling is an expansion of conventional distance sampling (CDS), a standard method applied to aerial survey designs for wildlife, where HDS allows for modeling spatial variation in abundance and detection probability using environmental covariates and can account for changing population demographics. We foundN‐mixture models produced similar parameter estimates to HDS with both models inferring a population increase between years, which was consistent with independently available estimates for this population (2014N‐mixture = 402 [CI: 303.8–515.27], and HDS = 391 [CI: 297.67–504.63]; 2016N‐mixture = 732 [CI: 572.89–924.22], and HDS = 708 [CI: 552.45–893.89]). Estimates from both models were sensitive to the sample unit size selected in an open population framework. We recommend using ecological (e.g., home range size) and statistical (e.g., sample size) considerations when selecting a sample unit size that reflects the movement ecology of a species and evaluating the sensitivity of parameters to sample unit size. In our study,N‐mixture models and HDS models afforded a practical field approach and analytical methodology that resulted in precise estimation in a population of unmarked deer over time. When used with aerial surveys in terrestrial systems where distance sampling methods may be difficult to implement,N‐mixture models can address observer error and estimate populations for conservation and management goals without marking individual animals.

Sample size considerations for matched-pair cluster randomization design with incomplete observations ofbinary outcomes.

Multiple public health and medical research studies have applied matched-pair cluster randomization design to the evaluation of the intervention and/or prevention effects. One of the most common and severe problems faced by researchers when conducting cluster randomized trials (CRTs) is incomplete observations, which are associated with various reasons causing the individuals to discontinue participating in the trials. Although statistical methods to remedy the problems of missing data have already been proposed, there are still methodological gaps in research concerning the determination of sample size in matched-pair CRTs with incomplete binary outcomes. One conventional method for adjusting for missing data in the sample size determination is to divide the sample size under complete data by the expected follow-up rate. However, such crude adjustment ignores the impact of the structure and strength of correlations regarding both outcome data and missing data mechanism. This article provides a closed-form sample size formula for matched-pair CRTs with incomplete binary outcomes, which appropriately accounts for different missing patterns and magnitudes as well as the effects of matching and clustering on the outcome and missing data. The generalized estimating equation (GEE) approach treats incomplete observations as missing data in a marginal logistic regression model, which flexibly accommodates various types of intraclass correlation, missing patterns, and missing proportions. In the presence of missing data, the proposed GEE sample size method provides higher accuracy as compared with the conventional method. The performance of the proposed method is assessed by simulation studies. This article also illustrates how the proposed method can be used to design a real-world matched-pair CRT to examine the effect of a team-based approach on controlling blood pressure (BP).

The Tokophobia Severity Scale (TSS): measurement model, power and sample size considerations

ABSTRACT Objective: To examine the measurement model of the Tokophobia Severity Scale and consider issues of statistical power and sample size from the original instrument development study. Background: Fear of childbirth (FoC) and tokophobia represents an area of increasing concern within perinatal mental health research and clinical practice. Existing measures of the FoC have been criticised due to either measurement inconsistencies, difficulties in scoring or practical clinical application. Attempting to address these limitations, researchers developed the Tokophobia Severity Scale (TSS). A fundamental assumption underpinning the use of the TSS is unidimensionality, however this assertion may have been based on sub-optimal sample size and approach taken to factor structure determination. Method: Parallel analysis (PA), principal components analysis (PCA), exploratory factor analysis (EFA), power analysis and sample size calculation using a reconstruction of the original dataset from published summary data. Results: Following replication of the original PCA, a three-factor model was found to offer a significantly better fit to data than a unidimensional model. Power analysis suggested the original study was underpowered. Conclusion: The TSS remains a promising tool but assumptions regarding its measurement model are based on an inadequate sample size. Sample sizes for a sufficiently powered study indicated.

Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study.

BackgroundA very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human individuals infected with Plasmodium vivax. The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P. vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival.Methods and findingsWe examined spleen tissue in 22 mostly untreated individuals naturally exposed to P. vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from individuals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or sample size considerations in both patient cohorts for this demanding approach.In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P. vivax, 13 P. falciparum, and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P. vivax-infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P. vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P. vivax- than in P. falciparum-infected spleens. Histological analyses revealed 96% of P. vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted.ConclusionsImmature CD71+ reticulocytes and splenic P. vivax-infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P. vivax infection. Findings provide insight into P. vivax-specific adaptions that have evolved to maximise survival and replication in the spleen.

ECOG-ACRIN EAA181: Effective quadruplet utilization after treatment evaluation (EQUATE)—a randomized phase 3 trial for newly diagnosed multiple myeloma (NDMM) not intended for early autologous transplantation.

TPS8052 Background: The monoclonal antibody (MoAb) daratumumab (dara) has been approved for treatment of newly diagnosed Multiple Myeloma (NDMM) in combination with lenalidomide (len) and dexamethasone (DRd) in patients who are not eligible to undergo stem cell transplantation (SCT). Ongoing trials are examining the role of adding bortezomib (Btz) to DRd, but it remains unclear if all patients benefit from a quadruplet regimen. Availability of sensitive assays to detect measurable/minimal residual disease (MRD) in MM and emerging data demonstrating significant prognostic value for attaining MRD negativity, offers an unprecedented opportunity to develop individualized treatment approaches. An important question is to identify who benefits from adding a fourth drug to the MoAb-IMiD triplet, thus individualizing therapy based on depth of response. We hypothesize that prolonged intensive therapy with the addition of Btz for consolidation and maintenance after DRd induction therapy for NDMM will improve survival outcomes with a more pronounced effect when used in MRD positive patients. Methods: Patients with NDMM, R-ISS Stage I or II, who are not eligible to undergo SCT or those willing to defer SCT to first relapse and have not received more than 1 cycle of any NDMM therapy will be enrolled, provided they have measurable disease, adequate organ and marrow function, have received no more than once cycle of therapy for MM and significant peripheral neuropathy or chronic obstructive pulmonary disease. Importantly, a dominant clone should be identified by lymphotrack assay for future MRD monitoring. Once enrolled, induction therapy will be in 28 day cycles consisting of daraSC (1800 mg) weekly for 2 cycles, every other week for cycles 3-6 and then every 4 weeks for 9 cycles, along with len 25 mg days 1-21 of each cycle and dex 40 mg (20 mg for those > 75 years) weekly. At end of 9 cycles (induction), patients will undergo MRD testing by next generation sequencing and will be classified into MRD positive or negative subgroups. Using MRD as an integral biomarker, the trial employs a randomized biomarker-stratified design as proposed by Freidlin et al. to determine efficacy for each MRD subgroup. Patients will be stratified by MRD status and R-ISS stage and randomized to receive 9 cycles of consolidation with DRd, without (control arm) or with (experimental arm) Btz (1.3 mg/m2 weekly for 3 of 4 weeks), followed by DR maintenance until progression The primary endpoint is consolidation OS. Sample size considerations rest on estimates of MRD subgroup prevalence at the end of induction and operating characteristics establishing the treatment effect within the MRD positive subgroup as primary and MRD negative subgroup as key secondary. The total accrual goal is 1450 patients. Clinical trial information: NCT04566328.

Remind Me Again: Physician Response to Web Surveys: The Effect of Email Reminders Across 11 Opinion Survey Efforts at the American Board of Internal Medicine from 2017 to 2019.

For survey researchers, physicians in the United States are a difficult-to-reach subgroup. The purpose of this study is to quantify the effect of email reminders on web-based survey response rates targeting physicians. We conducted a retrospective analysis of 11 American Board of Internal Medicine surveys from 2017 to 2019. We compute aggregate response rates for the periods between weekly email contacts across the 11 surveys, while controlling for survey time to complete, physician age, gender, region, board certification status, and initial exam performance. The overall predicted response rate after six weekly email contacts was 23.7%, 95% CI: (17.1%, 33.0%). Across the 11 surveys, we found response rate for the first period to be 8.9%, 95% CI: (6.5%, 12.2%). We observed a 50% decrease in response from the first to the second period, which had a 4.4%, 95% CI: (3.2%, 6.2%), response rate. The third and fourth response periods yielded similar response rates of 3.0%, 95% CI: (2.3%, 3.9%) and 3.3%, 95%CI: (2.4%, 4.6%), respectively. The fifth and sixth response periods yielded similar response rates of 2.2%, 95%CI: (1.5%, 3.3%) and 1.9%, 95% CI: (1.3%, 2.7%), respectively. The results were further stratified into different levels of participant survey interest, and are helpful for cost and sample size considerations when designing a physician survey.

Sample size considerations for mid-season estimates from a large influenza vaccine effectiveness network in the United States

IntroductionMid-season influenza vaccine effectiveness (VE) estimates are a useful tool to help guide annual influenza vaccine strain selection, vaccine policy, and public health messaging. We propose using a sample size-driven approach with data-driven inputs for publication of mid-season influenza VE. MethodsWe used pooled inputs for VE by (sub)type and average vaccine coverage by age groups using data from eight seasons of the US Influenza VE Network to calculate sample sizes needed to estimate mid-season VE. ResultsWe estimate that 135 influenza-positive cases would be needed to detect an overall VE of 40% with 55% vaccine coverage among test-negative controls. Larger sample sizes would be required to produce reliable estimates specifically against influenza A/H3N2 and for older age groups. ConclusionUsing an existing network, most of the recent influenza seasons in the US would facilitate valid mid-season VE estimates using the proposed sample sizes for broad age groupings.

Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

BackgroundAttention‐deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD’s etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes.MethodsUsing the large ENIGMA‐ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks.ResultsExploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case–control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men.ConclusionsOur results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case–control differences appear more pronounced at least in some of the subgroups.

A potential role of fecal oxalate-degrading activity in oxalate homeostasis in end-stage renal disease patients; a descriptive pilot study

Introduction: End-stage renal disease (ESRD) patients have significant differences in plasma oxalic acid (POx) concentration under the same treatment conditions. Objectives: In the present study, we adopted the method of redoximetric titration with a KMnO4 solution to evaluate the effect of total fecal oxalate-degrading activity (ODA) on oxalate homeostasis in ESRD patients which has never been reported before. Patients and Methods: A total of 56 participants were enrolled in this cross-sectional pilot study, including 24 healthy volunteers (a control reference group) and 32 ESRD patients. Among the ESRD patients, there were 21 hemodialysis (HD) and 11 peritoneal dialysis (PD) patients. Total ODA in fecal samples as well as POx concentration, daily urinary oxalate (UOx) and PD effluent oxalate excretion were determined. Cohen’s d was computed to calculate the effect size using post-hoc analysis. Results: Total ODA in fecal microbiota ranged from -23 to 24%/0.01 g of feces and was statistically higher in healthy volunteers compared with the ESRD patients. The ESRD patients with positive total fecal ODA status had higher UOx excretion level and lower POx concentration compared with the patients with negative total fecal ODA status. Cohen’s d effect size was 1.99 and 1.05, respectively. Total fecal ODA was an independent risk factor associated with POx elevation in the ESRD patients. Conclusion: Our pilot study firstly demonstrated a potential role of total fecal ODA in oxalate homeostasis in ESRD patients. The results might be useful for determining sample size considerations and providing groundwork for future research projects.

Sample size and power considerations for cluster randomized trials with count outcomes subject to right truncation.

Cluster randomized trials (CRTs) are widely used in epidemiological and public health studies assessing population-level effect of group-based interventions. One important application of CRTs is the control of vector-borne disease, such as malaria. However, a particular challenge for designing these trials is that the primary outcome involves counts of episodes that are subject to right truncation. While sample size formulas have been developed for CRTs with clustered counts, they are not directly applicable when the counts are right truncated. To address this limitation, we discuss two marginal modeling approaches for the analysis of CRTs with truncated counts and develop two corresponding closed-form sample size formulas to facilitate the design of such trials. The proposed sample size formulas allow investigators to explore the power under a large number of scenarios without computationally intensive simulations. The proposed formulas are validated in extensive simulations. We further explore the implication of right truncation on power and apply the proposed formulas to illustrate the power calculation for a malaria control CRT where the primary outcome is subject to righttruncation.

Sample size considerations for matched-pair cluster randomization design with incomplete observations of continuous outcomes

Matched-pair cluster randomization design is becoming increasingly used in clinical and health behavioral studies. Investigators often encounter incomplete observations in the data collected. Statistical inference for matched-pair cluster randomization design with incomplete observations has been extensively studied in literature. However, sample size method for such study design is sparsely available. We propose a closed-form sample size formula for matched-pair cluster randomization design with continuous outcomes, based on the generalized estimating equation approach by treating incomplete observations as missing data in a marginal linear model. The sample size formula is flexible to accommodate different correlation structures, missing patterns, and magnitude of missingness. In the presence of missing data, the proposed method would lead to a more accurate sample size estimation than the crude adjustment method. Simulation studies are conducted to evaluate the finite-sample performance of the proposed sample size method under various design configurations. We use bias-corrected variance estimators to address the issue of inflated type I error when the number of clusters per group is small. A real application example of physical fitness study in Ecuadorian adolescents is presented for illustration.

Evaluation of diagnostic tests for low prevalence diseases: a statistical approach for leveraging real-world data to accelerate the study

ABSTRACT The evaluation of diagnostic tests usually involves statistical inference for its sensitivity. As sensitivity is defined as the probability that the test result will be positive when the target condition is present, the key study design consideration of sample size is the determination of the number of subjects with the target condition such that the estimation has adequate precision, or the hypothesis testing has adequate power. Traditionally, one may rely on prospective screening of subjects to obtain the required sample size, which means that if the prevalence of the disease is very low, a large number of subjects would need to be screened, increasing the study duration and cost. In this paper, we consider the possibility of substantially reducing the length and cost of a clinical study by leveraging subjects from a real-world data (RWD) source, focusing specifically on the diagnostic test for the cancer of interest. Using the propensity score methodology, we developed a procedure which ensures that the real-world subjects being leveraged are similar to their prospectively enrolled counterparts, thereby making the leveraging more justified. The procedure allows the down-weighting of the real-world subjects, which can be achieved by either using a Frequentist’s method based on the composite likelihood or a Bayesian method based on the power prior. The proposed approach can be applied to the evaluation of any diagnostic test and it is not limited to the current clinical study regarding a cancer diagnostic test. Notably, this paper is in close alignment with a recently released draft framework by the Medical Device Innovation Consortium (MDIC) on real-world clinical evidence and in vitro diagnostics, being a showcase of appropriately leveraging real-world data in diagnostic test evaluation for diseases with low prevalence to support regulatory decision-making.

Considerations of sample size in chemistry education research: numbers do count but context matters more!

A question which often arises for chemistry education researchers, and is also frequently raised by reviewers of Chemistry Education Research and Practice (CERP) articles, is whether a research data sample size (N) is big enough? However, the answer to this question is more complicated than a simple ‘yes’ or ‘no’! In fact, there is substantial discussion of this issue within research literature which can make it even harder for a researcher to decide.

Real-World Use of Maintenance Therapy and Associated Outcomes Following Autologous Stem Cell Transplant in US Patients with Newly Diagnosed Multiple Myeloma

Background: In patients with newly-diagnosed multiple myeloma (NDMM) who receive frontline autologous stem cell transplantation (ASCT), maintenance therapy (MT) following ASCT has been shown to delay disease progression and death. Current National Comprehensive Cancer Network (NCCN) guidelines also recommend MT for patients with MM, including the use of lenalidomide, bortezomib-based regimens, or ixazomib. However, there is limited evidence on the use and outcomes associated with MT in contemporary real-world patients. The present study assessed MT treatment patterns and clinical outcomes in a real-world US cohort of patients with NDMM following ASCT. Methods: This retrospective, observational cohort study included NDMM patients initially diagnosed from 2011-2018 who received frontline ASCT. Patients were selected from the US Flatiron Health (FH) deidentified electronic health record (EHR)-derived database, which includes longitudinal patient-level data from over 265 community-based and academic cancer clinics across the US. To ensure capture of post-ASCT consolidation and MT, the study sample was restricted to patients who resumed contact within the FH network within 60 days following ASCT. Patients were excluded if they received treatment within the context of a clinical trial or had a second transplant within 180 days of their initial ASCT. Patients were classified as receiving MT if (during the 180-day post-transplant period) they initiated treatment with an NCCN-recommended MT regimen or continued to receive a subset of the antimyeloma agents used as induction regimen following ASCT and consolidation (if any). Key measures included baseline demographic and clinical characteristics, antimyeloma treatments (frontline induction, consolidation, and MT, if any), and clinical outcomes (time to next myeloma treatment [TTNT] and overall survival [OS]). Treatment duration and clinical outcomes were analyzed using Kaplan-Meier estimators and Cox regression to account for right-censoring. For TTNT and OS, follow-up began on the earlier of the ASCT date + 90 days or start of MT and continued through the dataset cut-off date (May 30, 2020) or loss to follow-up; TTNT and OS were estimated for patients receiving lenalidomide maintenance [R-MT], bortezomib maintenance [V-MT], or no MT, but was not estimated for other MT regimens due to sample size considerations. Results: 528 NDMM patients (median age 61 years, interquartile range [IQR]: 55, 68; 45.3% female) underwent ASCT and met study inclusion criteria. The most common induction regimens were bortezomib-lenalidomide-dexamethasone (VRd; 60.0%), lenalidomide-dexamethasone (Rd; 16.3%), and cyclophosphamide-bortezomib-dexamethasone (CyBorD; 10.2%). Following ASCT, 7.2% of patients received consolidation therapy and 74.2% received MT (lenalidomide monotherapy [R-MT]: 58.7%; bortezomib monotherapy [V-MT]: 7.6%; other MT: 7.8%). Median duration of MT was 18.0 months (IQR: 8.7, 29.1), and was similar for R-MT and V-MT (median 18.9 and 18.6 months, respectively). MT use increased from 69.3% to 79.0% from 2011-2013 to 2017-2018 (P=0.04); in addition, patients were more likely to have received VRd as induction across different MT (Table 1). R-MT and V-MT were both associated with longer TTNT relative to no MT (unadjusted hazard ratios [HRs]: 0.29 [95% CI: 0.22, 0.38] and 0.39 [95% CI: 0.25, 0.61], respectively) (Figure 1A). Improvements in OS were marginally significant with R-MT (HR: 0.58 [95% CI: 0.33, 1.00]) and nonsignificant with V-MT (HR: 0.86 [95% CI: 0.35, 2.11]) relative to no MT (Figure 1B); however, the OS estimates are characterized by low precision due to the relatively small number of events observed. Limitations included lack of documentation of reasons for treatment in the FH database, and use of consolidation and MT were inferred from observed treatment patterns; therefore, misclassification of MT was possible. Conclusions: This analysis demonstrates that MT use following ASCT has increased in routine clinical practice in the US since 2011-2013, with R-MT being the most common regimen followed by V-MT. However, a substantial proportion of patients did not receive MT. MT use in real-world settings was associated with longer TTNT and a trend toward longer OS. Exploration of additional maintenance regimens to improve clinical outcomes is warranted in this patient population. Disclosures Ammann: Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Tang:Janssen: Current Employment. Kampfenkel:Janssen: Current Employment. Sharma:Mu Sigma: Current Employment; Janssen: Other: Contractor. Lee:Janssen: Current Employment. Kaila:Janssen Scientific Affairs: Current Employment. Fu:Janssen: Current Employment. Gray:Janssen: Current Employment. He:Janssen: Current Employment.

A meta-analysis of the influence of ADRB2 genetic polymorphisms on albuterol (salbutamol) therapy in patients with asthma.

The associations of 2 nonsynonymous single nucleotide polymorphisms (Arg16Gly and Gln27Glu) in the adrenoceptor β2 (ADRB2) gene with response after albuterol use are conflicting. We conducted a meta-analysis to examine the cumulative evidence of the effects of these 2 variants on percent forced expiratory volume in 1 second (FEV1.0%) after albuterol use in asthma patients. We conducted a comprehensive literature search using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify studies examining the association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% shortly after albuterol administration. The individual study results were combined with weights based on the inverse variance method. This systematic review was registered in the PROSPERO (registration number: CRD42019074554). Among 273 initial studies identified, 7 studies met the inclusion criteria for quantitative evaluation. Results of the overall meta-analysis indicated no statistically significant mean difference of FEV1.0% between genotypes of Arg16Gly and Gln27Glu. In subgroup analyses, significant associations were found for Arg16Gly GG (vs AA) among studies where no methacholine bronchoconstriction was conducted (mean difference, -3.92; 95% confidence interval, -7.29 to -0.54; I2 = 0%), and for Arg16Gly GG (vs GA) among studies that included patients with no comorbidities (mean difference, -1.93; 95% confidence interval, -3.77 to -0.10; I2 = 0%). Synthesis of the studies to date shows weak evidence for an association between ADRB2 Arg16Gly and Gln27Glu and FEV1.0% after albuterol use, results of which underscore significant heterogeneity across studies and the need for careful design and sample size considerations.

Prediction models for COVID-19 clinical decision making

Prediction models for COVID-19 clinical decision making

Effects on Mouse Food Consumption After Exposure to Bedding from Sick Mice or Healthy Mice

Control mice housed in the same room as mice with pancreatic ductal adenocarcinoma (PDAC) demonstrate decreased food intake coincident with the cachexia experienced by the mice with PDAC. Mice are considered an empathetic species, and we hypothesized that the reduced food intake in normal mice was an "empathy state" that was mediated by olfactory cues. Naïve male and female C57BL/6 mice were exposed to soiled bedding from mice experiencing PDAC induced cachexia or from control mice in the PDAC study. Body weight, food intake, and food spillage were measured across 48 h. Statistically significant differences in food consumption were found at various time points in both positive and negative directions for the 2 bedding conditions, and the direction of effect was opposite for males and females. Although analysis of data from previous PDAC studies showed differences in food spillage between PDAC mice and their controls, in this study we found no correlation between food consumption and food spillage based on bedding type. Disruption of food intake due to the "empathy state" requires testing larger numbers of animals to attain appropriate statistical power, which is contrary to the goal of using fewer animals. Empathy effects require careful consideration of sample size and cautious interpretation of results. This study also highlights the importance of sex as a biologic variable and why quantifying food spillage is important in studies of food intake.

Appraising Minimum Effect of Standardized Contrasts in ANCOVA Designs: Statistical Power, Sample Size, and Covariate Imbalance Considerations

The concepts and implementation of standardized mean differences and minimum effect tests have been emphasized in ANOVA. The corresponding processes and implications are, however, not yet well explicated in the context of ANCOVA. To enhance the usefulness of ANCOVA, this article describes the minimum effect tests of standardized contrast as a valuable alternative to the hypothesis testing of no effect difference and the conventional evaluation of unstandardized effects in ANCOVA. Power and sample size procedures are developed to accommodate covariate randomness and imbalance for randomized and nonrandomized designs. The data from a clinical study of comparing two treatments for gingivitis are used to illustrate the application of the suggested approaches. The emphases of numerical appraisal are on the merit of minimum effect detection in comparative analysis and the influence of covariate feature in power and sample size computation. The proposed power and sample size calculations improve upon approximate formulas by fully accounting for the stochastic property and intrinsic disparity of the covariate variables. Computer algorithms are available for calculating the p-value, power level, and sample size of one- and two-sided minimum effect tests.