Simultaneous relaxometry and morphometry of human brain structures with 3D magnetic resonance fingerprinting: a multicenter, multiplatform, multifield-strength study.

Relaxation times and morphological information are fundamental magnetic resonance imaging-derived metrics of the human brain that reflect the status of the underlying tissue. Magnetic resonance fingerprinting (MRF) enables simultaneous acquisition of T1 and T2 maps inherently aligned to the anatomy, allowing whole-brain relaxometry and morphometry in a single scan. In this study, we revealed the feasibility of 3D MRF for simultaneous brain structure-wise morphometry and relaxometry. Comprehensive test-retest scan analyses using five 1.5-T and three 3.0-T systems from a single vendor including different scanner types across 3 institutions demonstrated that 3D MRF-derived morphological information and relaxation times are highly repeatable at both 1.5 T and 3.0 T. Regional cortical thickness and subcortical volume values showed high agreement and low bias across different field strengths. The ability to acquire a set of regional T1, T2, thickness, and volume measurements of neuroanatomical structures with high repeatability and reproducibility facilitates the ability of longitudinal multicenter imaging studies to quantitatively monitor changes associated with underlying pathologies, disease progression, and treatments.

Association of longitudinal pet ownership with wheezing in 3-year-old children using the distributed lag model: the Japan Environment and Children's Study.

BACKGROUND: Time-varying exposures like pet ownership pose challenges for identifying critical windows due to multicollinearity when modeled simultaneously. The Distributed Lag Model (DLM) estimates critical windows for time-varying exposures, which are mainly continuous variables. However, applying complex functions such as high-order splines and nonlinear functions within DLMs may not be suitable for situations with limited time points or binary exposure, such as in questionnaire surveys. OBJECTIVES: (1) We examined the estimation performance of a simple DLM with fractional polynomial function for time-varying binary exposures through simulation experiments. (2) We evaluated the impact of pet ownership on childhood wheezing onset and estimate critical windows. METHODS: (1) We compared logistic regression including time-varying exposure in separate models, in one model simultaneously, and using DLM. For evaluation, we employed bias, empirical standard error (EmpSE), and mean squared error (MSE). (2) The Japan Environment and Children's Study (JECS) is a prospective birth cohort study of approximately 100,000 parent-child pairs, registered across Japan from 2011 to 2014. We applied DLM to the JECS data up to age 3. The estimated odds ratios (OR) were considered to be within critical windows when they were significant at the 5% level. RESULTS: (1) DLM and the separate model exhibited lower bias compared to the simultaneously model. Additionally, both DLM and the simultaneously model demonstrated lower EmpSEs than the separate model. In all scenarios, DLM had lower MSEs than the other methods. Specifically, where critical windows is clearly present and exposure correlation is high, DLM showed MSEs about 1/2 to 1/200 of those of other models. (2) Application of DLM to the JECS data showed that, unlike other models, a significant exposure effect was observed only between the ages of 0 and 6 months. During that periods, the highest ORs were 1.07 (95% confidence interval, 1.01 to 1.14) , observed between the ages of 2 and 5 months. CONCLUSIONS: (1) A simple DLM improves the accuracy of exposure effect and critical windows estimation. (2) 0-6 months may be the critical windows for the effect of pet ownership on the wheezing onset at 3 years.

A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer.

PURPOSE: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups. METHODS: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated. RESULTS: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33-0.78) and 29% (HR: 0.71, 95% CI 0.49-1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29-0.74). CONCLUSIONS: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

Gradient Boosted Tree Approaches for Mapping European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Onto 5-Level Version of EQ-5D Index for Patients With Cancer.

OBJECTIVES: This study aimed to develop direct and response mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 onto the 5-level version of EQ-5D index based on the gradient boosted tree (GBT), a promising modern machine learning method. METHODS: We used the Quality of Life Mapping Algorithm for Cancer study data (903 observations from 903 patients) for training GBTs and testing their predictive performance. In the Quality of Life Mapping Algorithm for Cancer study, patients with advanced solid tumor were enrolled, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 5-level version of EQ-5D were simultaneously evaluated. The Japanese value set was used for direct mapping, whereas the Japanese and US value sets were used for response mapping. We trained the GBTs in the training data set (80%) with cross-validation and tested the predictive performance measured by the root mean squared error (RMSE), mean absolute error (MAE), and mean error in the test data set (20%). RESULTS: The RMSE and MAE in the test data set were larger in the GBT approaches than in the previously developed regression-based approaches. The mean error in the test data set tended to be smaller in the GBT approaches than in the previously developed regression-based approaches. CONCLUSIONS: The predictive performances in the RMSE and MAE did not improve by the GBT approaches compared with regression approaches. The flexibility of the GBT approaches had the potential to reduce overprediction and underprediction in poor and good health, respectively. Further research is needed to establish the role of machine learning methods in mapping a nonpreference-based measure onto health utility.

Impacts of the preceding cancer-specific health-related quality of life instruments on the responses to the subsequent EQ-5D-5L.

BACKGROUND: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. METHODS: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. RESULTS: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was - 0.036 (95% CI - 0.065 to - 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003) and - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003), respectively. CONCLUSIONS: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire.

Rigid real-time prospective motion-corrected three-dimensional multiparametric mapping of the human brain.

PURPOSE: To develop a rigid real-time prospective motion-corrected multiparametric mapping technique and to test the performance of quantitative estimates. METHODS: Motion tracking and correction were performed by integrating single-shot spiral navigators into a multiparametric imaging technique, three-dimensional quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS). The spiral navigator was optimized, and quantitative measurements were validated using a standard system phantom. The effect of motion correction on whole-brain T1 and T2 mapping under different types of head motion during the scan was evaluated in 10 healthy volunteers. Finally, six patients with Parkinson's disease, which is known to be associated with a high prevalence of motion artifacts, were scanned to evaluate the effectiveness of our method in the real world. RESULTS: The phantom study demonstrated that the proposed motion correction method did not introduce quantitative bias. Improved parametric map quality and repeatability were shown in volunteer experiments with both in-plane and through-plane motions, comparable to the no-motion ground truth. In real-life validation in patients, the approach showed improved parametric map quality compared to images obtained without motion correction. CONCLUSIONS: Real-time prospective motion-corrected multiparametric relaxometry based on 3D-QALAS provided robust and repeatable whole-brain multiparametric mapping.

Minimal important differences of EORTC QLQ-C30 for metastatic breast cancer patients: Results from a randomized clinical trial.

PURPOSE: To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. METHODS: The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. RESULTS: We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from - 7 to - 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from - 5 to - 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. CONCLUSION: We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30.

Prevalence, Incidence Rate, and Risk Factors of Medication-Related Osteonecrosis of the Jaw in Patients With Osteoporosis and Cancer: A Nationwide Population-Based Study in Japan.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severe adverse event of antiresorptive agents. However, the precise prevalence and factors associated with the development of MRONJ remain unknown. The present study was performed to describe the prevalence, incidence rate, and risk factors of developing MRONJ. METHODS: We conducted a population-based retrospective cohort study using the National Database of Health Insurance, an administrative claims database of all patients in Japan. We identified patients who newly began using antiresorptive drugs from April 2015 to December 2018. The primary outcome was the development of MRONJ. We calculated the prevalence and incidence rate of MRONJ and performed a time-dependent Cox proportional hazard regression analysis to examine risk factors for developing MRONJ. RESULTS: We identified 2,819,310 patients who newly used antiresorptive drugs during the study period. Of these patients, 2,664,104 (94.5%) had osteoporosis and 155,206 had cancer. Among the patients with osteoporosis, 1,603 (0.06%) developed MRONJ; the incidence rate was 22.9 per 100,000 person-years. Among the patients with cancer, 2,274 (1.47%) developed MRONJ; the incidence rate was 1,231.7 per 100,000 person-years. The occurrence of MRONJ was associated with poor oral conditions (including tooth extraction), age, male sex, drug type, concomitant drug use, comorbidities, cancer type, and geographic location. CONCLUSIONS: The overall prevalence and incidence rate were low, but they were still higher than those in previous studies. Poor oral conditions were more closely related to the development of MRONJ than other factors. These findings suggest that improving poor oral hygiene may be essential to prevent MRONJ.

Impact of Body Weight Gain on the Incidence of Nonalcoholic Fatty Liver Disease in Nonobese Japanese Individuals.

INTRODUCTION: We aimed to investigate the effect of recent short-term weight gain on the incidence of nonalcoholic fatty liver disease (NAFLD) in nonobese (body mass index < 25 kg/m) participants. METHODS: This retrospective cohort study included nonobese individuals who participated in an annual health checkup between 2008 and 2018 in Tokyo, Japan. We estimated the multivariable adjusted hazard ratio for the development of NAFLD diagnosed via ultrasound after a 3-kg unit gain in weight measured at a 2-year landmark time point postbaseline. Multivariable adjustments included weight change from the age of 20 and other relevant confounding factors. Sensitivity analyses using additional landmark time points at 1, 3, 4, and 5 years postbaseline and time-dependent Cox proportional hazards regressions were performed. RESULTS: Among the 27,064 nonobese participants (142,699 person years of follow-up), 2,895 were diagnosed with NAFLD. Approximately 90% of the patients with NAFLD maintained their nonobese status before disease diagnosis. The adjusted hazard ratio for the development of NAFLD (for a 3-kg unit of weight gain) at the 2-year landmark time point postbaseline was 1.60 (95% confidence interval, 1.46-1.76) in nonobese men and 1.66 (95% confidence interval, 1.51-1.83) in nonobese women. This association was maintained in the sensitivity analyses. DISCUSSION: Recent short-term weight gain is an independent risk factor for NAFLD development in nonobese men and women. Clinicians should be mindful of the association between weight gain and NAFLD onset, even in the nonobese population.

Effect of Diameter and Number of Hepatocellular Carcinomas on Survival After Resection, Transarterial Chemoembolization, and Ablation.

INTRODUCTION: Most studies predicting survival after resection, transarterial chemoembolization (TACE), and ablation analyzed diameter and number of hepatocellular carcinomas (HCCs) as dichotomous variables, resulting in an underestimation of risk variation. We aimed to develop and validate a new prognostic model for patients with HCC using largest diameter and number of HCCs as continuous variables. METHODS: The prognostic model was developed using data from patients undergoing resection, TACE, and ablation in 645 Japanese institutions. The model results were shown after balanced using the inverse probability of treatment-weighted analysis and were externally validated in an international multi-institution cohort. RESULTS: Of 77,268 patients, 43,904 patients, including 15,313 (34.9%) undergoing liver resection, 13,375 (30.5%) undergoing TACE, and 15,216 (34.7%) undergoing ablation, met the inclusion criteria. Our model (http://www.u-tokyo-hbp-transplant-surgery.jp/about/calculation.html) showed that the 5-year overall survival (OS) in patients with HCC undergoing these procedures decreased with progressive incremental increases in diameter and number of HCCs. For patients undergoing resection, the inverse probability of treatment-weighted-adjusted 5-year OS probabilities were 10%-20% higher compared with patients undergoing TACE for 1-6 HCC lesions <10 cm and were also 10%-20% higher compared with patients undergoing ablation when the HCC diameter was 2-3 cm. For patients undergoing resection and TACE, the model performed well in the external cohort. DISCUSSION: Our novel prognostic model performed well in predicting OS after resection and TACE for HCC and demonstrated that resection may have a survival benefit over TACE and ablation based on the diameter and number of HCCs.

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial.

PURPOSE: To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. METHODS: In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24). RESULTS: The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] - 0.3 to 1.6) at 1 year and 0.9 (95% CI - 1.0 to 2.8) at 3 years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3 years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548). CONCLUSION: This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer. TRIAL REGISTRATION NUMBER: NCT01104935 (first posted April 16, 2010).

Sensitivity analysis for subsequent treatments in confirmatory oncology clinical trials: A two-stage stochastic dynamic treatment regime approach.

Subsequent treatments can result in a difficulty in interpretation of the overall survival results in confirmatory oncology clinical trials. To complement the intention-to-treat (ITT) analysis affected by subsequent treatment patterns unintentional in the trial protocol, several causal methods targeting the per-protocol effect have been proposed. When two or more types of subsequent treatments are allowed in the trial protocol, however, these methods cannot answer clinical questions such as how sensitive the ITT analysis result is to higher or lower proportions of each subsequent treatment allowed in the trial protocol than observed, and to what extent ITT analysis result is generalizable to subsequent treatment patterns other than observed one. To answer these clinical questions, we propose a sensitivity analysis method for subsequent treatments using the inverse probability of treatment weighting method for stochastic dynamic treatment regimes (DTRs). We formulate oncology clinical trials with subsequent treatments as two-stage designs in which initial treatments are randomized, but subsequent treatments are observational. In this formulation, we use stochastic DTRs to simulate specific proportions of each subsequent treatment and compare an initial experimental treatment with an initial control treatment under various proportions of each subsequent treatment. We applied our proposed method to a motivating randomized noninferiority trial for metastatic breast cancer. Simulation results are also reported to show the usefulness of the proposed method.

Sodium-glucose cotransporter-2 inhibitors and the risk of urinary tract infection among diabetic patients in Japan: Target trial emulation using a nationwide administrative claims database.

AIM: To assess the risk of urinary tract infection (UTI) occurrence associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use relative to biguanide use in diabetes in a population-based cohort study using a target trial emulation framework. METHODS: Using a Japanese nationwide administrative claims database, we constructed a cohort of patients aged ≥40 years who were dispensed SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors or biguanides between April 2014 and March 2015. For computational ease, we randomly sampled 100% of SGLT2 inhibitor users, 3% of DPP-4 inhibitor users, and 20% of biguanide users; new antidiabetic drug initiators were analysed. We estimated the intention-to-treat (ITT) hazard ratios (HRs) of UTI with inverse probability of treatment (IPT)-weighted Cox's proportional hazards models that ignored subsequent treatment changes. Treatment weights were computed using patient sex, age, medications, medical history and hospitalization history. We also estimated per-protocol (PP) HRs using IPT- and inverse probability of censoring-weighted Cox's models that adjusted for nonrandom treatment changes. RESULTS: We analysed 11 364 SGLT2 inhibitor initiators, 9035 DPP-4 inhibitor initiators, and 10 359 biguanide initiators. When compared with biguanide initiators, SGLT2 inhibitor initiators had a crude HR of 1.14 (95% confidence interval [CI] 1.05-1.24), an ITT HR of 0.94 (95% CI 0.86-1.03), and a PP HR of 0.90 (95% CI 0.78-1.03); and DPP-4 inhibitor initiators had a crude HR of 1.13 (95% CI 1.04-1.23), an ITT HR of 0.85 (95% CI 0.77-0.94), and a PP HR of 0.83 (95% CI 0.71-0.95). CONCLUSION: Use of SGLT2 inhibitors or DPP-4 inhibitors did not increase the risk of UTI compared with biguanide use. Accounting for treatment changes did not substantially influence the estimated effects.

A simulation study of regression approaches for estimating risk ratios in the presence of multiple confounders.

BACKGROUND: Risk ratio is a popular effect measure in epidemiological research. Although previous research has suggested that logistic regression may provide biased odds ratio estimates when the number of events is small and there are multiple confounders, the performance of risk ratio estimation has yet to be examined in the presence of multiple confounders. METHODS: We conducted a simulation study to evaluate the statistical performance of three regression approaches for estimating risk ratios: (1) risk ratio interpretation of logistic regression coefficients, (2) modified Poisson regression, and (3) regression standardization using logistic regression. We simulated 270 scenarios with systematically varied sample size, the number of binary confounders, exposure proportion, risk ratio, and outcome proportion. Performance evaluation was based on convergence proportion, bias, standard error estimation, and confidence interval coverage. RESULTS: With a sample size of 2500 and an outcome proportion of 1%, both logistic regression and modified Poisson regression at times failed to converge, and the three approaches were comparably biased. As the outcome proportion or sample size increased, modified Poisson regression and regression standardization yielded unbiased risk ratio estimates with appropriate confidence intervals irrespective of the number of confounders. The risk ratio interpretation of logistic regression coefficients, by contrast, became substantially biased as the outcome proportion increased. CONCLUSIONS: Regression approaches for estimating risk ratios should be cautiously used when the number of events is small. With an adequate number of events, risk ratios are validly estimated by modified Poisson regression and regression standardization, irrespective of the number of confounders.

G-estimation of structural nested restricted mean time lost models to estimate effects of time-varying treatments on a failure time outcome.

G-estimation of structural nested models (SNMs) plays an important role in estimating the effects of time-varying treatments with appropriate adjustment for time-dependent confounding. As SNMs for a failure time outcome, structural nested accelerated failure time models (SNAFTMs) and structural nested cumulative failure time models have been developed. The latter models are included in the class of structural nested mean models (SNMMs) and are not involved in artificial censoring, which induces several difficulties in g-estimation of SNAFTMs. Recently, restricted mean time lost (RMTL), which corresponds to the area under a distribution function up to a restriction time, is attracting attention in clinical trial communities as an appropriate summary measure of a failure time outcome. In this study, we propose another SNMM for a failure time outcome, which is called structural nested RMTL model (SNRMTLM) and describe randomized and observational g-estimation procedures that use different assumptions for the treatment mechanism in a randomized trial setting. We also provide methods to estimate marginal RMTLs under static treatment regimes using estimated SNRMTLMs. A simulation study evaluates finite-sample performances of the proposed methods compared with the conventional intention-to-treat and per-protocol analyses. We illustrate the proposed methods using data from a randomized controlled trial for cardiovascular disease with treatment changes. G-estimation of SNRMTLMs is a useful tool to estimate the effects of time-varying treatments on a failure time outcome.

What Is a Valid Mapping Algorithm in Cost-Utility Analyses? A Response From a Missing Data Perspective.

OBJECTIVES: Although numerous mapping algorithms from a non-preference-based measure to a target health utility measure have been developed and applied in cost-utility analyses (CUAs), conditions for a mapping algorithm to work well in a CUA are still unclear. In this research, we formulate the mapping problem as a missing data problem and clarify these conditions. METHODS: We defined a valid mapping algorithm based on the purpose of mapping (ie, not for prediction but for CUA), and derived a sufficient set of conditions for a valid mapping algorithm. We also conducted a simulation study to investigate properties of a mapping algorithm under situations where the conditions are satisfied and violated. RESULTS: The derived sufficient conditions indicate that the complete overlap of the source measure with the target health utility measure is important and that a covariate that is omitted from a mapping algorithm but has an effect on the target health utility measure not captured by the source measure may invalidate a mapping algorithm. The conditions cannot be verified from data in a CUA but can be supported using external data. A simulation study showed that when at least 1 of the 3 conditions was violated, a mapping algorithm provided biased health utility estimates in a CUA, and that prediction accuracy did not necessarily reflect performance of a mapping algorithm in a CUA. CONCLUSION: The derived conditions provide a fundamental basis for better practices in developing and selecting a mapping algorithm.

Mapping EORTC QLQ-C30 and FACT-G onto EQ-5D-5L index for patients with cancer.

BACKGROUND: To develop direct and indirect (response) mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy General (FACT-G) onto the EQ-5D-5L index. METHODS: We conducted the QOL-MAC study where EQ-5D-5L, EORTC QLQ-C30, and FACT-G were cross-sectionally evaluated in patients receiving drug treatment for solid tumors in Japan. We developed direct and indirect mapping algorithms using 7 regression methods. Direct mapping was based on the Japanese value set. We evaluated the predictive performances based on root mean squared error (RMSE), mean absolute error, and correlation between the observed and predicted EQ-5D-5L indexes. RESULTS: Based on data from 903 and 908 patients for EORTC QLQ-C30 and FACT-G, respectively, we recommend two-part beta regression for direct mapping and ordinal logistic regression for indirect mapping for both EORTC QLQ-C30 and FACT-G. Cross-validated RMSE were 0.101 in the two methods for EORTC QLQ-C30, whereas they were 0.121 in two-part beta regression and 0.120 in ordinal logistic regression for FACT-G. The mean EQ-5D-5L index and cumulative distribution function simulated from the recommended mapping algorithms generally matched with the observed ones except for very good health (both source measures) and poor health (only FACT-G). CONCLUSIONS: The developed mapping algorithms can be used to generate the EQ-5D-5L index from EORTC QLQ-C30 or FACT-G in cost-effectiveness analyses, whose predictive performance would be similar to or better than those of previous algorithms.

The Number of Events per Confounder for Valid Estimation of Risk Difference Using Modified Least-Squares Regression.

Risk difference is a relevant effect measure in epidemiologic research. Although it is well known that when there are few events per confounder, logistic regression is not suitable for confounding control, it is not clear how many events per confounder are required for valid estimation of risk difference using linear binomial models. Because the maximum likelihood method has a convergence problem, we investigated the number of events per confounder necessary to validly estimate risk difference using modified least-squares regression in a simulation. We simulated 864 scenarios, according to the number of confounders (2-20), the number of events per confounder (2-12), marginal risk (0.5%-40%), exposure proportion (20% and 40%), and 3 sizes of risk difference. Our simulation showed that modified least-squares regression provided unbiased risk difference-regardless of the number of events per confounder-and reliable confidence intervals when more than 5 events were expected in the exposed and in the unexposed, irrespective of the number of events per confounder. We illustrated the modified least-squares regression analysis using perinatal epidemiologic data. Modified least-squares regression is considered to be a useful analytical tool for rare binary outcomes relative to the number of confounders.

Patient-Reported Outcome Results from the Open-Label Randomized Phase III SELECT BC Trial Evaluating First-Line S-1 Therapy for Metastatic Breast Cancer.

OBJECTIVE: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. METHODS: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. RESULTS: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. CONCLUSION: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting.

BACKGROUND AND AIMS: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. METHODS: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. RESULTS: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. CONCLUSIONS: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA.