HBcrAg-based risk score performs better than the HBV DNA-based scores for HCC prediction in grey zone patients who are HBeAg-negative.

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients. Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development. Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts. Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management. Impact and implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative.

Muscle strength in ostensibly healthy non-diabetic subjects.

BACKGROUND/PURPOSE: Sarcopenia and decreased muscle strength (dynapenia) are emerging health issues. However, the study exploring muscle strength changes of both upper and lower limbs at the same time among all age groups is rare. This study aims to investigate the muscle strength and to establish a muscle strength norm of an ostensibly healthy non-diabetic Asian population. METHODS: From 2018 June to 2020 March, subjects (aged from 20 to <80 years old) undergoing health checkup in Good Liver Medical Examination Center and National Taiwan University Hospital Geriatrics and Gerontology Department were enrolled. A battery of muscle power examinations including handgrip strength (HGS), five times sit-to-stand test (5TSTS), and one-leg standing test (OLST) were performed. RESULTS: A total of 183 participants was enrolled, consisting of 92 females and 91 males. The finding shows the strongest HGS, best 5TSTS, and the longest OLST of both genders appeared in the 20-29-year-old group. Age, gender, and palm length are significantly related to HGS, whereas age is the only factor affecting 5TSTS and OLST. It revealed a progressive decline during ageing process, especially after age 60. Finally, Z-score and T-score norms of these were established. CONCLUSION: These data will be useful as normal controls for muscle strength of specific disease groups. The application of the cutoffs from these data and their comparisons with the recommended cutoffs from various guidelines worth further exploration.

Low Hepatitis B Core-Related Antigen Levels Correlate Higher Spontaneous Seroclearance of Hepatitis B Surface Antigen in Chronic Hepatitis B Patients With High Hepatitis B Surface Antigen Levels.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core-related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg. METHODS: We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL. RESULTS: There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P < .001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16-3.27). In contrast to the late decline of HBsAg levels (5-9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P < .001) in patients achieving undetectable HBcrAg levels. CONCLUSIONS: Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance.

Using the Countermovement Jump Metrics to Assess Dynamic Eccentric Strength: A Preliminary Study.

Background: This study aimed to determine the validity and reliability of the countermovement jump (CMJ) as a dynamic eccentric (Ecc) strength test. Methods: Thirty-three college male student-athletes were recruited to participate in this study. The participants first performed CMJs with the second consisting of one repetition maximum back squat (1RM-BS) test. CMJ and 1RM-BS tests were performed on twin force plates. Results: The CMJ had significant correlations with the Ecc peak force (EccPF), and Ecc mean force (EccMF) of 1RM-BS, respectively (r = 0.61−0.69). Moreover, all parameters had a coefficient of variation (CV) < 10%. The intraclass correlation coefficient (ICC) values were moderate to excellent for each metric using the CMJ (0.94−0.97). The 1RM-BS and CMJ EccPF, EccMF Bland-Altman bias estimate variance ratio is 1.31−1.67, showing a moderate-large correlation in the Bland-Altman plot. Conclusions: CMJ ECC phase kinetics were associated with the 1RM-BS EccPF and EccMF. The CMJ can be an alternative tool for eccentric dynamic strength assessment.

Effect of Acute Judo Training on Countermovement Jump Performance and Perceived Fatigue among Collegiate Athletes.

This study focused on the effect of acute Judo training on countermovement jump (CMJ) performance and perceived fatigue among a group of highly trained collegiate judo athletes. Twenty male judo athletes participated in this study (age: 20.65 ± 1.22 years, weight: 84.17 ± 28.45 kg). Participants were assessed for CMJperformance changes before, immediately after (0 h), 12 h after, and 24 h after judo training (JT) using unloaded CMJ(CMJunloaded) and loaded CMJ(CMJloaded). All the jumps were performed on a force plate, and the force-time curves were collected for further analysis. Respondents' perceptions were evaluated using the modified rating of perceived exertion (mRPE) before, after (0 h), 12 h, and 24 h after JT. CMJparameters were analyzed at four measured points using a one-way repeated analysis of variance. Effect sizes (ES) and percentage changes before versus 24 h after JT were calculated for comparison. Associations between the CMJparameters and mRPE were analyzed using the Pearson product-moment correlation. The ratio of flight time to contact time significantly decreased, whereas the eccentric duration, concentric duration, and total duration significantly increased (p < 0.05) in both CMJs 24 h after JT. Compared with CMJunloaded, CMJloaded had a significantly lower (p < 0.05) flight time, jump height, peak velocity, and peak power. The mRPE and CMJloaded peak velocity showed moderate- to high-level negative correlation results both 0 and 24 h after training (r = -0.543, p < 0.05; r = -0.479, p < 0.05). In this study, we only observed the effect of fatigue on the neuromuscular (NM) system 24 h after JT. CMJloaded height may help to better determine fatigue state compared with CMJunloaded. According to the results, the neuromuscular effects of fatigue were not observed until 24 h after a single high-intensity training. Therefore, when arranging high-intensity special training or strength and conditioning training, one should reduce the volume of training appropriately to avoid fatigue accumulation and reduce the risk of sports injuries.

Three-Stage Pooled Plasma Hepatitis C Virus RNA Testing for the Identification of Acute HCV Infections in At-Risk Populations.

Timely diagnosis and treatment of hepatitis C virus (HCV) infection may prevent its transmission. We evaluated the performance and cost reductions of the pooled plasma HCV RNA testing strategy to identify acute HCV infections among people living with HIV (PLWH). PLWH with sexually transmitted infections, elevated aminotransferases within the past 6 months or past HCV infections (high-risk) and those without (low-risk) were enrolled prospectively. Participants underwent three-stage pooled plasma HCV RNA testing every 12 to 24 weeks until detection of HCV RNA or completion of a 48-week follow-up. The three-stage strategy combined 20 individual specimens into a stage 1 pool, 5 individual specimens from the stage 1 pool that tested positive for HCV RNA in the stage 2 mini-pool, followed by testing of individual specimens of the stage 2 mini-pool tested positive for HCV RNA. A simulation was constructed to investigate the cost reductions and pooled sensitivity and specificity under different combinations of HCV prevalence and pool/mini-pool sizes. Between June 25, 2019 and March 31, 2021, 32 cases of incident HCV viremia were identified in 760 high-risk PLWH that were enrolled 834 times, giving an incidence rate of 56.6 per 1000 person-years of follow-up (PYFU). No cases of HCV viremia were identified in 557 low-risk PLWH during a total of 269.2 PYFU. Simulation analysis suggested that this strategy could reduce HCV RNA testing cost by 50% to 86% with HCV viremia prevalence of 1% to 5% and various pooled sizes despite compromised pooled sensitivity. This pooled plasma HCV RNA testing strategy is cost-saving to identify acute HCV infections in high-risk populations with HCV viremia prevalence of 1% to 5%. IMPORTANCE Our three-stage pooled plasma HCV RNA testing successfully identified HCV viremia in high-risk PLWH with a testing cost reduction of 84.5%. Simulation analysis offered detailed information regarding the selection of pool and mini-pool sizes in settings of different HCV epidemiology and the performance of HCV RNA testing to optimize the cost reduction.

Use of likelihood estimates for variances for the design and evaluation of multiregional clinical trials with heterogeneous variances.

Globalized drug development studies, such as multiregional clinical trials (MRCTs), have attracted much attention due to their ability to expedite drug development and shorten the time lag of drug release. While observing the overall effect of a new drug, the region-specific effects to support drug registration in constituent regions can also be evaluated. Several challenges arise in conducting MRCTs, such as the heterogeneity in the variability of the primary endpoint across regions. However, most of the existing statistical methods assume a common variability, which may not be valid in practice due to differences across regions (eg, diversities in ethnicity or disparities in medical culture/practice). We present a statistical method for the design and evaluation of MRCTs to consider the heterogeneous variability across regions. We assessed the overall sample size requirement and addressed the region-specific sample size determination to establish the consistency of treatment effects between the specific region and the entire group. We demonstrate the proposed approach with numerical examples.

Impact of Efavirenz Mid-dose Plasma Concentration on Long-Term Weight Change Among Virologically Suppressed People Living With HIV.

BACKGROUND: Pharmacogenetic studies have shown that slow and intermediate metabolizers of efavirenz (EFV) gained less weight compared with extensive metabolizers. It is hypothesized that increased EFV exposure suppresses weight gain. We investigated the effect of EFV mid-dose plasma concentration (C12) on long-term weight change among virologically suppressed people living with HIV (PLWH). METHODS: Participants in a prospective EFV pharmacokinetic study were included if they had been taking EFV-containing combination antiretroviral therapy for more than 240 weeks and had 3 or more weight measurements. The weight changes and time to ≥5% of weight gain over 192 weeks were compared between PLWH with higher and those with lower EFV C12 (using mean population C12 as the cutoff). EFV C12 and CYP2B6 516G>T polymorphism were examined in generalized estimating equations and in a Cox proportional hazards model for associations with weight gain, after adjustments for age, sex, companion antiretroviral agent, CD4 lymphocyte count, and plasma HIV RNA. RESULTS: One hundred eighteen PLWH were included. PLWH with higher EFV C12 had less mean weight gain compared with those with lower C12 after 192 weeks (-0.09 vs +1.58 kg, P = 0.033). PLWH with higher C12 were less likely to gain ≥5% weight in Kaplan-Meier analysis (P = 0.0003). In both generalized estimating equations and Cox proportional hazards models, a higher EFV C12 was associated with less weight gain, while CYP2B6 516G>T was not, after adjustments made for confounding factors. CONCLUSIONS: Our findings support that increased EFV exposure was associated with less weight gain.

Tolerance interval testing for assessing accuracy and precision simultaneously.

Tolerance intervals have been recommended for simultaneously validating both the accuracy and precision of an analytical procedure. However, statistical inferences for the corresponding hypothesis testing are scarce. The aim of this study is to establish a whole statistical inference for tolerance interval testing, including sample size determination, power analysis, and calculation of p-value. More specifically, the proposed method considers the bounds of a tolerance interval as random variables so that a bivariate distribution can be derived. Simulations confirm the theoretical properties of the method. Furthermore, an example is used to illustrate the proposed method.

Use of a two-sided tolerance interval in the design and evaluation of biosimilarity in clinical studies.

In assessing biosimilarity between two products, the question to ask is always "How similar is similar?" Traditionally, the equivalence of the means between products is the primary consideration in a clinical trial. This study suggests an alternative assessment for testing a certain percentage of the population of differences lying within a prespecified interval. In doing so, the accuracy and precision are assessed simultaneously by judging whether a two-sided tolerance interval falls within a prespecified acceptance range. We further derive an asymptotic distribution of the tolerance limits to determine the sample size for achieving a targeted level of power. Our numerical study shows that the proposed two-sided tolerance interval test controls the type I error rate and provides sufficient power. A real example is presented to illustrate our proposed approach.

Use of a tolerance interval approach as a statistical quality control tool for traditional Chinese medicine.

Raw materials for traditional Chinese medicine (TCM) are often from different resources and its final product may also be made by different sites. Therefore, variabilities from different resources such as site-to-site or within site component-to-component may be expected. Consequently, test for consistency in raw materials, in-process materials, and/or final product has become an important issue in the quality control (QC) process in TCM development. In this paper, a statistical QC process for raw materials and/or the final product of TCM is proposed based on a two sided [Formula: see text]-content, [Formula: see text]-confidence tolerance interval. More specifically, we construct the tolerance interval for a random-effects model to assess the QC of TCM products from different regions and possibly different product batches. The products can be claimed to be consistency when the constructed tolerance interval is within the permitted range. Given the region and batch effects, sample sizes can also be calculated to ensure the desired measure of goodness. An example is presented to illustrate the proposed approach.

Operational Experiences in China and Statistical Issues on the Conduct of Clinical Trials During the COVID-19 Pandemic.

The COVID-19 outbreak is impacting clinical trials in many ways, such as patient recruitment, data collection and data analysis. To proceed in this difficult time, the adoption of new technologies and new approaches for conducting clinical trials needs to be accelerated. Simultaneously, regulatory agencies such as the US FDA and EMA have issued guidance to help the pharmaceutical industry conduct clinical trials of medical products during the COVID-19 pandemic. In this article, we will address some statistical issues and operational experiences in the conduction of clinical trials during the COVID-19 pandemic. Specifically, we will share experiences in the applications of remote clinical trials in China. Statistical issues related to protocol modifications caused by COVID-19 will be raised.

Use of interval estimations in design and evaluation of multiregional clinical trials with continuous outcomes.

Multiregional clinical trials have been accepted in recent years as a useful means of accelerating the development of new drugs and abridging their approval time. The statistical properties of multiregional clinical trials are being widely discussed. In practice, variance of a continuous response may be different from region to region, but it leads to the assessment of the efficacy response falling into a Behrens-Fisher problem-there is no exact testing or interval estimator for mean difference with unequal variances. As a solution, this study applies interval estimations of the efficacy response based on Howe's, Cochran-Cox's, and Satterthwaite's approximations, which have been shown to have well-controlled type I error rates. However, the traditional sample size determination cannot be applied to the interval estimators. The sample size determination to achieve a desired power based on these interval estimators is then presented. Moreover, the consistency criteria suggested by the Japanese Ministry of Health, Labour and Welfare guidance to decide whether the overall results from the multiregional clinical trial obtained via the proposed interval estimation were also applied. A real example is used to illustrate the proposed method. The results of simulation studies indicate that the proposed method can correctly determine the required sample size and evaluate the assurance probability of the consistency criteria.

Prediction of plasma efavirenz concentrations among HIV-positive patients taking efavirenz-containing combination antiretroviral therapy.

We investigated the predictors of plasma mid-dose concentrations (C12) of efavirenz by enrolling 456 HIV-positive patients who had received 2 nucleos(t)ide reverse-transcriptase inhibitors plus efavirenz (600 mg daily) for 2 weeks or longer and had their CYP2B6 516G>T polymorphism and efavirenz C12 determined. The median efavirenz C12 was 2.41 mg/L (IQR, 1.93-3.14). In analysis of covariance models, patients with CYP2B6 516GT and TT genotypes compared to those with GG genotype had higher efavirenz C12 (for GT genotype, an increase by 0.976 mg/L [95%CI, 0.765-1.188], and TT genotype, 4.871 mg/L [95%CI, 4.126-5.616]), while per 10-kg increment in weight decreased C12 by 0.199 mg/L (95%CI, 0.111-0.287). Models incorporating CYP2B6 516G>T polymorphism and weight had moderate predictive values in predicting efavirenz C12 ≥ 2 mg/L (ROC area under curve = 0.706 [95%CI, 0.656-0.756]). In the absence of CYP2B6 516G>T polymorphism, weight ≤58 kg provided better predictabilities for efavirenz C12 ≥ 2 mg/L (probability, 77.1% [95%CI, 69.0-83.5%] for weight = 50 kg and 70.6% [95%CI, 64.1-76.4%] for weight = 58 kg).

An approach for sample size determination of average bioequivalence based on interval estimation.

In 1992, the US Food and Drug Administration declared that two drugs demonstrate average bioequivalence (ABE) if the log-transformed mean difference of pharmacokinetic responses lies in (-0.223, 0.223). The most widely used approach for assessing ABE is the two one-sided tests procedure. More specifically, ABE is concluded when a 100(1 - 2α) % confidence interval for mean difference falls within (-0.223, 0.223). As known, bioequivalent studies are usually conducted by crossover design. However, in the case that the half-life of a drug is long, a parallel design for the bioequivalent study may be preferred. In this study, a two-sided interval estimation - such as Satterthwaite's, Cochran-Cox's, or Howe's approximations - is used for assessing parallel ABE. We show that the asymptotic joint distribution of the lower and upper confidence limits is bivariate normal, and thus the sample size can be calculated based on the asymptotic power so that the confidence interval falls within (-0.223, 0.223). Simulation studies also show that the proposed method achieves sufficient empirical power. A real example is provided to illustrate the proposed method. Copyright © 2017 John Wiley & Sons, Ltd.

Highly Facet-Dependent Photocatalytic Properties of Cu2 O Crystals Established through the Formation of Au-Decorated Cu2 O Heterostructures.

This work confirms the presence of a large facet-dependent photocatalytic activity of Cu2 O crystals through sparse deposition of gold particles on Cu2 O cubes, octahedra, and rhombic dodecahedra. Au-decorated Cu2 O rhombic dodecahedra and octahedra showed greatly enhanced photodegradation rates of methyl orange resulting from a better separation of the photogenerated electrons and holes, with the rhombic dodecahedra giving the best efficiency. Au-Cu2 O core-shell rhombic dodecahedra also displayed a better photocatalytic activity than pristine rhombic dodecahedra. However, Au-deposited Cu2 O cubes, pristine cubes, and Au-deposited small nanocubes bound by entirely {100} facets are all photocatalytically inactive. X-ray photoelectron spectra (XPS) showed identical copper peak positions for these Au-decorated crystals. Remarkably, electron paramagnetic resonance (EPR) measurements indicated a higher production of hydroxyl radicals for the photoirradiated Cu2 O rhombic dodecahedra than for the octahedra, but no radicals were produced from photoirradiated Cu2 O cubes. The Cu2 O {100} face may present a high energy barrier through its large band edge bending and/or electrostatic repulsion, preventing charge carriers from reaching to this surface. The conventional photocatalysis model fails in this case. The facet-dependent photocatalytic differences should be observable in other semiconductor systems whenever a photoinduced charge-transfer process occurs across an interface.

Synthesis of Small Au-Ag Core-Shell Cubes, Cuboctahedra, and Octahedra with Size Tunability and Their Optical and Photothermal Properties.

Aqueous phase synthesis of small Au-Ag core-shell nanocubes, cuboctahedra, and octahedra is achieved through the deposition of Ag shells on small octahedral Au cores. These nanocrystals show efficient photothermal activity and can assemble into supercrystals.

Quality of life changes in patients undergoing treatment for hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. One of the primary treatment goals for incurable advanced cases is to prolong quality of life (QoL). Thus, to determine which HCC therapies may be linked to a more favorable QoL, we assessed the association between QoL changes and different treatments in HCC patients. METHODS: We analyzed a non-randomized multicenter longitudinal study, which included 171 patients treated with surgery (n = 53), ablation (n = 53) or embolization (n = 65) from seven centers: four Asian and three European sites. All participants completed the EORTC QLQ-C30 and QLQ-HCC18 questionnaires before and after treatment. Propensity scores were calculated and used in addition to race for adjustment in the logistic regression model to account for the confounding effects of patient characteristics including age, gender, race, employment, living with family, at least one comorbid condition, years since diagnosis, prior treatment history, BCLC stage, Child-Pugh grade, cirrhosis, bilirubin levels and QoL score before treatment. RESULTS: After adjustment for confounders, patients tended to have higher odds of QoL deterioration when treated with ablation versus embolization (dyspnea: p = 0.019; appetite loss: p = 0.018; body image: p = 0.035) or ablation versus surgery (dyspnea: p = 0.099; appetite loss: p = 0.100; body image: p = 0.038). CONCLUSIONS: There were significant differences in QoL deterioration across different treatment groups. This information may assist patients and providers when selecting patient-centered treatment approaches for HCC.

An Investigation Into the Relationship Between Maximum Isometric Strength and Vertical Jump Performance.

Research has demonstrated a clear relationship between dynamic strength and vertical jump (VJ) performance; however, the relationship of isometric strength and VJ performance has been studied less extensively. The aim of this study was to determine the relationship between isometric strength and performance during the squat jump (SJ) and countermovement jump (CMJ). Twenty-two male collegiate athletes (mean ± SD; age = 21.3 ± 2.9 years; height = 175.63 ± 8.23 cm; body mass = 78.06 ± 10.77 kg) performed isometric midthigh pulls (IMTPs) to assess isometric peak force (IPF), maximum rate of force development, and impulse (IMP) (I100, I200, and I300). Force-time data, collected during the VJs, were used to calculate peak velocity, peak force (PF), peak power (PP), and jump height. Absolute IMTP measures of IMP showed the strongest correlations with VJ PF (r = 0.43-0.64; p ≤ 0.05) and VJ PP (r = 0.38-0.60; p ≤ 0.05). No statistical difference was observed in CMJ height (0.33 ± 0.05 m vs. 0.36 ± 0.05 m; p = 0.19; ES = -0.29) and SJ height performance (0.29 ± 0.06 m vs. 0.33 ± 0.05 m; p = 0.14; ES = -0.34) when comparing stronger to weaker athletes. The results of this study illustrate that absolute IPF and IMP are related to VJ PF and PP but not VJ height. Because stronger athletes did not jump higher than weaker athletes, dynamic strength tests may be more practical methods of assessing the relationships between relative strength levels and dynamic performance in collegiate athletes.

Sample size determination for individual bioequivalence inference.

Statistical criterion for evaluation of individual bioequivalence (IBE) between generic and innovative products often involves a function of the second moments of normal distributions. Under replicated crossover designs, the aggregate criterion for IBE proposed by the guidance of the U.S. Food and Drug Administration (FDA) contains the squared mean difference, variance of subject-by-formulation interaction, and the difference in within-subject variances between the generic and innovative products. The upper confidence bound for the linearized form of the criterion derived by the modified large sample (MLS) method is proposed in the 2001 U.S. FDA guidance as a testing procedure for evaluation of IBE. Due to the complexity of the power function for the criterion based on the second moments, literature on sample size determination for the inference of IBE is scarce. Under the two-sequence and four-period crossover design, we derive the asymptotic distribution of the upper confidence bound of the linearized criterion. Hence the asymptotic power can be derived for sample size determination for evaluation of IBE. Results of numerical studies are reported. Discussion of sample size determination for evaluation of IBE based on the aggregate criterion of the second moments in practical applications is provided.