Prognostic factors of health care-associated bloodstream infection in adult patients ≥40 years of age.

We investigated 401 geriatric patients and 453 middle-aged patients with health care-associated bloodstream infection (HABSI) at a medical center during January-December 2014. Compared with middle-aged patients, the geriatric group had higher 30-day mortality (31.2% vs 23.4%, P = .01). Body mass index, serum albumin concentration, Charlson comorbidity index score, vancomycin-resistant Enterococcus bacteremia, and high C-reactive protein levels predict poor outcomes for HABSI among adult patients.

Addressing Loss of Efficiency Due to Misclassification Error in Enriched Clinical Trials for the Evaluation of Targeted Therapies Based on the Cox Proportional Hazards Model.

A key feature of precision medicine is that it takes individual variability at the genetic or molecular level into account in determining the best treatment for patients diagnosed with diseases detected by recently developed novel biotechnologies. The enrichment design is an efficient design that enrolls only the patients testing positive for specific molecular targets and randomly assigns them for the targeted treatment or the concurrent control. However there is no diagnostic device with perfect accuracy and precision for detecting molecular targets. In particular, the positive predictive value (PPV) can be quite low for rare diseases with low prevalence. Under the enrichment design, some patients testing positive for specific molecular targets may not have the molecular targets. The efficacy of the targeted therapy may be underestimated in the patients that actually do have the molecular targets. To address the loss of efficiency due to misclassification error, we apply the discrete mixture modeling for time-to-event data proposed by Eng and Hanlon [8] to develop an inferential procedure, based on the Cox proportional hazard model, for treatment effects of the targeted treatment effect for the true-positive patients with the molecular targets. Our proposed procedure incorporates both inaccuracy of diagnostic devices and uncertainty of estimated accuracy measures. We employed the expectation-maximization algorithm in conjunction with the bootstrap technique for estimation of the hazard ratio and its estimated variance. We report the results of simulation studies which empirically investigated the performance of the proposed method. Our proposed method is illustrated by a numerical example.

Association of quality of life with laboratory measurements and lifestyle factors in community dwelling older people in Taiwan.

OBJECTIVES: Little is known about the influence of routine laboratory measurements and lifestyle factors on generic quality of life (QOL) at older ages. We aimed to study the relationship between generic QOL and laboratory measurements and lifestyle factors in community dwelling older Chinese people. METHODS: We conducted a cross-sectional analysis. Six hundred and ninety nine elders were randomly selected from the examinees of the annual health examination in Taipei City, Taiwan. Blood, urine and stool of the participants were examined and lifestyle data were collected. Participants completed the CASP-19 (control, autonomy, self-realization, pleasure) questionnaire, a 19-item QOL scale. The relationship between QOL and laboratory results and lifestyle factors was explored, using multiple linear regression and profile analysis. RESULTS: The mean age of the participants was 75.5 years (SD = 6.5), and 49.5% were female. Male gender standardized ß coefficients (ß = 0.122) and exercise habit (ß = 0.170) were associated with a better QOL, whereas advanced age (ß = -0.242), blurred vision (ß = -0.143), depression (ß = -0.125), central obesity (ß = -0.093), anemia (ß = -0.095), rheumatoid arthritis (ß = -0.073), Parkinsonism (ß = -0.079), malignancy (ß = -0.086) and motorcycle riding (ß = -0.086) were associated with a lower QOL. Profile analysis revealed that young-old males, social drinkers, regular exercisers and car drivers had the best QOL (all p < 0.001). CONCLUSION: Of the many laboratory measurements, only anemia was associated with the lower QOL. By contrast, several lifestyle factors, such as social drinking, exercise habit and car driving, were associated with better QOL, whereas abdominal obesity and motorcycle riding were associated with lower QOL.

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.

Applications of the bayesian prior information to evaluation of equivalence of similar biological medicinal products.

In 2014, there are a number of patents of best-selling biotech drugs around the world about to expire. Large commercial interests will inevitably set off international competition among major pharmaceutical companies. The European Union, the United States, and other countries with advanced medical techniques have paid a high degree of attention to biological similarity (biosimilarity) for drug development and market management and have started to take corresponding measures. Because of the diverse definitions of biosimilarity between countries, which can determine whether the medicines on sale are in the review of the base grant, the competent authority will also encounter varying degrees of standards. Governments should review the corresponding guidelines as soon as possible because many countries around the world have actively amended the law in response to management need of biological similarity. The similarity of biological drugs should be assessed by clinical trial under current regulations. Pharmaceutical companies try to lower the cost of generic drugs to increase the competitiveness of their products. To reduce the number of subjects in the clinical trials for development of generic drugs, we refer to the clinical trial for evaluation of bridging studies. Hsiao et al. (2007) has proposed the use of Bayes method in evaluation of bridging studies. Prior information on the original region is used to reduce the number of subjects to lower the cost of biosimilar drug development. Take the results of the approval biologics as a priori information, and the information is appropriate to be embedded into the model evaluating the similar products in order to reduce the sample size required for the assessment of the test sample.

An approximate approach to sample size determination in bioequivalence testing with multiple pharmacokinetic responses.

The approval of generic drugs requires the evidence of average bioequivalence (ABE) on both the area under the concentration-time curve and the peak concentration Cmax . The bioequivalence (BE) hypothesis can be decomposed into the non-inferiority (NI) and non-superiority (NS) hypothesis. Most of regulatory agencies employ the two one-sided tests (TOST) procedure to test ABE between two formulations. As it is based on the intersection-union principle, the TOST procedure is conservative in terms of the type I error rate. However, the type II error rate is the sum of the type II error rates with respect to each null hypothesis of NI and NS hypotheses. When the difference in population means between two treatments is not 0, no close-form solution for the sample size for the BE hypothesis is available. Current methods provide the sample sizes with either insufficient power or unnecessarily excessive power. We suggest an approximate method for sample size determination, which can also provide the type II rate for each of NI and NS hypotheses. In addition, the proposed method is flexible to allow extension from one pharmacokinetic (PK) response to determination of the sample size required for multiple PK responses. We report the results of a numerical study. An R code is provided to calculate the sample size for BE testing based on the proposed methods.

Factors associated with falls among community-dwelling older people in Taiwan.

INTRODUCTION: Falls are common among older people. Previous studies have shown that falls were multifactorial. However, data regarding community-dwelling Chinese population are minimal. We aimed to study factors associated with falls among community-dwelling older Chinese people. MATERIALS AND METHODS: We conducted a cross-sectional study in a community hospital in Taiwan in 2010. Our sample included 671 elders from the 3680 examinees of the free annual Senior Citizens Health Examination. Participants were interviewed with a detailed questionnaire, and 317 elders were further invited for serum vitamin D tests. The main outcome was falls in the previous 12 months. Predictor variables included sociodemographic characteristics, lifestyle risk factors, body stature, frailty, serum 25 (OH) D levels, and medications. RESULTS: The mean age of the 671 participants was 75.7 ± 6.4 years old, and 48.7% of which were female. Fallers comprised 21.0% of the study population. In multivariate models, female gender (adjusted odds ratio (aOR): 2.32), loss of height in adulthood (aOR: 1.52), low body weight (aOR: 2.69), central obesity (aOR: 1.67), frailty (aOR: 1.56), polypharmacy (aOR: 2.18) and hyperglycaemia (aOR: 1.56) were factors associated with falls. Vitamin D insufficiency (serum 25 (OH) D levels <30 ng/mL) was not associated with falls (OR: 0.78; 95% CI, 0.38 to 1.60) (n = 317) in this study. CONCLUSION: Among community-dwelling older people in Taiwan, falls were mainly associated with female gender, polypharmacy, frailty, reduced body height, low body weight or central obesity, and hyperglycaemia. In addition to other risk factors, body stature should be considered as a novel risk factor when screening elders at risk for falls.

Statistical inference on censored data for targeted clinical trials under enrichment design.

For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures.

Quality of life (QOL) among community dwelling older people in Taiwan measured by the CASP-19, an index to capture QOL in old age.

There was no existing scale in Mandarin Chinese to specifically measure QOL in old age. We aimed to validate a Chinese Taiwan version of the CASP-19 (control, autonomy, self-realization, pleasure), a QOL questionnaire, in Taiwan. The existing CASP-19 Cantonese version was modified into Chinese Taiwan version and pilot tested. Data were then gathered from 699 older people. Score distribution, exploratory and confirmatory factor structure, reliability and clinical validity of the CASP-19 and its shortened version, the CASP-12, were examined. The mean age of the participants was 75.5 (standard deviation (SD) 6.5), and half (49.5%) were female. The mean CASP-19 score was 38.2 (range 11-56; SD 7.1), lower than that of Western countries. Exploratory factor analysis revealed an additional factor, 'participation' (CASPP-19). There was satisfactory internal consistency (Cronbach's α 0.63-0.85) for the subscales, except for the control domain. For the 19-item scale, the first order five-domain model (CASPP-19) yielded the best fit. For the CASP-12, first and second order original CASP-12 models performed equally well. There was an inverse relationship between the CASP total scores and frailty, chronic diseases, depressive disorders, living alone and fall events in the past 12months, supporting good clinical validity for all versions of the CASP scale (CASP-19, CASPP-19, original and new CASP-12). The original CASP-12 may be presently the best choice for use in China, Taiwan or other Mandarin-speaking populations due to its conciseness and model parsimony.

An approximate approach to sampling size determination for the equivalence hypothesis.

The equivalence hypothesis is the correct hypothesis to confirm whether the new test product conforms to the standard reference product. It has many applications to evaluation of generic drug products and other new clinical modalities. The two one-sided tests (TOST) procedure was proposed to test the equivalence hypothesis for two treatments. When the difference in population means between two treatments is not 0, the proportion of the type II error rate allocated to each of the two tails of the central t-distribution cannot be analytically determined. Hence, no close form of the exact sample size for the equivalence hypothesis is available. Currently only approximate formulas are proposed. The resulting sample sizes may provide either insufficient power or unnecessarily excessive power. We suggest an approximate approach with consideration of type II error rates for both one-sided hypotheses to determination of the sample size for the equivalence hypothesis. The results of a numerical study are reported. Remarks on the usage of different methods for the sample size determination for the equivalence hypothesis in practical applications are provided.

Immune gene expression profiles in swine inguinal lymph nodes with different viral loads of porcine circovirus type 2.

Porcine circovirus type 2 (PCV2) infection has been suggested as an acquired immunodeficiency disorder. However, the immunopathogenesis of PCV2 infection is still not fully clarified. In the present study, 35 inguinal lymph nodes (LNs) with different levels of PCV2 load obtained from postwaening multisystemic wasting syndrome (PMWS)-affected pigs and 7 from healthy subclinically PCV2-infected pigs were selected. The LNs were subsequently ranked by their PCV2 loads to mimic the progression of PCV2 infection-associated lesion development. The expressions of 96 selected immune genes in these LNs were assessed by the integration of several reverse transcription quantitative real-time polymerase chain reaction experiments. Hierarchical cluster analysis of the gene expression profiles resulted in 5 major clusters (A, B, C, D, and E). Different clusters of immune gene expression profiles were compatible with the divergent functions of various immune cell subpopulations. 61 out of 96 selected genes belonged to cluster C and were mainly involved in the activation of dendritic cells and B and T lymphocytes. The expression levels of these genes were generally up-regulated in the LNs obtained from PMWS-affected pigs with relatively lower PCV2 loads. However, the up-regulated level tended to reduce or turned into down-regulation as the PCV2 load increased. Genes belonging to cluster B, involved in T cell receptor signaling, became silenced as the PCV2 load increased. The expression profiles of macrophage-associated genes were either independent from or positively correlated with the PCV2 load, such as those in clusters A and E and in cluster D, respectively. In addition, the principle component analysis of the expression of the 96 selected genes in the 42 inguinal LNs revealed that 53.10% and 72.29% of the total data variants could be explained by the top-3 and top-7 principle components, respectively, suggesting that the disease development of PCV2 infection may be associated with a few major and some minor factors. In conclusion, assessment of immune gene expression profiles in LNs supports a close interaction between immune activation and suppression during the progression of PMWS development.

Application of the parallel line assay to assessment of biosimilar products based on binary endpoints.

Biological drug products are therapeutic moieties manufactured by a living system or organisms. These are important life-saving drug products for patients with unmet medical needs. Because of expensive cost, only a few patients have access to life-saving biological products. Most of the early biological products will lose their patent in the next few years. This provides the opportunity for generic versions of the biological products, referred to as biosimilar drug products. The US Biologic Price Competition and Innovation Act passed in 2009 and the draft guidance issued in 2012 provide an approval pathway for biological products shown to be biosimilar to, or interchangeable with, a Food and Drug Administration-licensed reference biological product. Hence, cost reduction and affordability of the biosimilar products to the average patients may become possible. However, the complexity and heterogeneity of the molecular structures, complicated manufacturing processes, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence between the biosimilar products and their corresponding reference product a great challenge for statisticians and regulatory agencies. To accommodate the stepwise approach and totality of evidence, we propose to apply a parallel assay to evaluate the extrapolation of the similarity in product characteristics such as doses or pharmacokinetic responses to the similarity in binary efficacy endpoints. We also report the results of simulation studies to evaluate the performance, in terms of size and power, of our proposed methods. We present numerical examples to illustrate the suggested procedures.

Statistical methods for bridging studies.

In 1998, the International Conference on Harmonization (ICH) published a guidance to facilitate the registration of medicines among ICH regions including the European Union, the United States, and Japan by recommending a framework for evaluating the impact of ethnic factors on a medicine's effect, such as its efficacy and safety at a particular dosage and dose regimen (ICH E5, 1998). The purpose of ICH E5 is not only to evaluate the ethnic factor influence on safety, efficacy, dosage, and dose regimen, but also more importantly to minimize duplication of clinical data and allow extrapolation of foreign clinical data to a new region. In this article, statistical methods for evaluation of bridging studies based on the concepts of consistency (Shih, 2001), reproducibility/generalizability (Shao and Chow, 2002), the weighted Z-tests for the design of bridging studies (Lan et al., 2005), and similarity between the new and original region based in terms of positive treatment effect (Hsiao et al., 2007) are studied. The relative merits and disadvantages of these methods are compared by several examples.

Relationship between dietary patterns and serum uric acid concentrations among ethnic Chinese adults in Taiwan.

The evidence for a relationship between dietary patterns and uric acid concentrations is scanty. Here, we used a validated food frequency questionnaire for an ethnic Chinese population in Taiwan to investigate the relationship between dietary patterns and uric acid concentrations. A cross-sectional study on 266 adults, who were interviewed with a 38-item food frequency questionnaire, was conducted and serum uric acid levels were measured. Three dietary patterns were derived from the questionnaire by exploratory factor analysis. Participants in the higher vegetable and fruit pattern quartiles were more likely to have a lower uric acid concentration (6.5 for the first, 5.7 for the second, 6.0 for the third, and 6.0 mg/dL for the fourth quartile, p = 0.030). For uric acid-prone patterns, as the quartiles increased, the adjusted mean uric acid concentrations increased significantly (5.88, 5.93, 5.99 and 6.38 mg/dL for each quartile, respectively, p = 0.04). However, the significance level was attenuated after adjusting for additional confounding factors. In conclusion, three dietary patterns were identified for ethnic Chinese in Taiwan, and the relationship between these dietary patterns and uric acid was not significant after adjustment.

An inferential procedure for the probability of passing the USP dissolution test.

Dissolution is one of the tests that is required and specified by the United States Pharmacopeia and National Formulary (USP/NF) to ensure that the drug products meet the standards of the identity, strength, quality, purity, and stability. The sponsors also establish the in-house specifications for the mean and standard deviation of the dissolution rates to guarantee a high probability of passing the USP/NF dissolution test. However, the USP/NF dissolution test is a complicated three-stage sampling plan that involves both the sample mean dissolution rate of all units and the dissolution rate of individual units. It turns out that the true probability of passing the USP/NF dissolution is formidable to compute analytically even when the population mean and variance of dissolution rates are known. It is not clear that previously proposed methods are the estimators of the true probability for passing the USP dissolution test. Therefore, we propose to employ a parametric bootstrap method in conjunction with the Monte Carlo simulation to obtain the sampling distribution of the estimated probabilities of passing the USP/NF dissolution test and hence the confidence interval for the passing probability. In addition, a procedure is proposed to test whether the true probability of passing the USP/NF dissolution test is greater than some specified value. A numerical example illustrates the proposed method. Copyright © 2011 John Wiley & Sons, Ltd.

Predicting healthcare utilization using a pharmacy-based metric with the WHO's Anatomic Therapeutic Chemical algorithm.

BACKGROUND: Automated pharmacy claim data have been used for risk adjustment on health care utilization. However, most published pharmacy-based morbidity measures incorporate a coding algorithm that requires the medication data to be coded using the US National Drug Codes or the American Hospital Formulary Service drug codes, making studies conducted outside the US operationally cumbersome. OBJECTIVE: This study aimed to verify that the pharmacy-based metric with the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) algorithm can be used to explain the variations in health care utilization. RESEARCH DESIGN: The Longitudinal Health Insurance Database of Taiwan's National Health Insurance enrollees was used in this study. We chose 2006 as the baseline year to predict the total cost, medication cost, and the number of outpatient visits in 2007. The pharmacy-based metric with 32 classes of chronic conditions was modified from a revised version of the Chronic Disease Score. RESULTS: The ordinary least squares (OLS) model and log-transformed OLS model adjusted for the pharmacy-based metric had a better R in concurrently predicting total cost compared with the model adjusted for Deyo's Charlson Comorbidity Index and Elixhauser's Index. The pharmacy-based metric models also provided a superior performance in predicting medication cost and number of outpatient visits. For prospectively predicting health care utilization, the pharmacy-based metric models also performed better than the models adjusted by the diagnosis-based indices. CONCLUSIONS: The pharmacy-based metric with the WHO ATC algorithm and the matching ATC codes were tested and found to be valid for explaining the variation in health care utilization.

A consistency approach to evaluation of bridging studies and multi-regional trials.

Recently, global drug developments have attracted much attention from sponsors as well as regulatory authorities. The ICH E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. On the other hand, a multi-regional trial may incorporate subjects from many regions around the world under the same protocol so that after showing the overall efficacy of a drug in all global regions, we can simultaneously evaluate the possibility of applying the overall trial results to each region and consequently support drug registration in each region. In this paper, we develop a consistency approach for assessment of similarity between a bridging study conducted in a new region and studies conducted in the original region. A statistical criterion is also established to assess the consistency between the region of interest and overall results in a multi-regional trial. The method for sample size determination for the bridging study is also proposed. Numerical examples illustrate applications of the proposed approaches in different scenarios.

An alternative phase II/III design for continuous endpoints.

The success rate of drug development has been declined dramatically in recent years and the current paradigm of drug development is no longer functioning. It requires a major undertaking on breakthrough strategies and methodology for designs to minimize sample sizes and to shorten duration of the development. We propose an alternative phase II/III design based on continuous efficacy endpoints, which consists of two stages: a selection stage and a confirmation stage. For the selection stage, a randomized parallel design with several doses with a placebo group is employed for selection of doses. After the best dose is chosen, the patients of the selected dose group and placebo group continue to enter the confirmation stage. New patients will also be recruited and randomized to receive the selected dose or placebo group. The final analysis is performed with the cumulative data of patients from both stages. With the pre-specified probabilities of rejecting the drug at each stage, sample sizes and critical values for both stages can be determined. As it is a single trial with controlling overall type I and II error rates, the proposed phase II/III adaptive design may not only reduce the sample size but also improve the success rate. An example illustrates the applications of the proposed phase II/III adaptive design.

Immunopathological characterization of porcine circovirus type 2 infection-associated follicular changes in inguinal lymph nodes using high-throughput tissue microarray.

The immunopathogenesis of porcine circovirus type 2 (PCV2) infection in conventional pigs is complicated by various environmental factors and individual variation and is difficult to be completely reproduced experimentally. In the present field-based study, a tissue microarray (TMA) consisting of a series of lymphoid follicles having different PCV2-loads was constructed using formalin-fixed and paraffin-embedded superficial inguinal lymph nodes (LNs) from 102 pigs. Using the TMA, a wide range of parameters, including co-infected viral pathogens, immune cell subsets, and cell apoptosis/proliferation activity by immunohistochemical (IHC) staining or in situ hybridization (ISH) were measured, characterized, and compared. The signal location and area extent of each parameter were interpreted by pathologists, semi-quantified by automated image analysis software, and analyzed statistically. The results herein demonstrated a significant negative correlation between PCV2 and CD79a (p<0.001) and a significant positive correlation between PCV2 and lysozyme (p<0.001) or TUNEL (p<0.001) using Pearson correlation analysis. The amount of porcine respiratory and reproductive syndrome virus (PRRSV) and porcine parvovirus antigens did not correlate with the tissue loads of PCV2 nucleic acid. Multiple regression analysis further predicted that PCV2 contributed major effects on CD79a, lysozyme, and TUNEL but PRRSV showed relatively less effects on these parameters. In addition, the total signal intensity of Ki67 (index of cell proliferation activity) did not change significantly among cases with different PCV2 loads; however, as the loading of PCV2 nucleic acid increased, the main contribution of Ki67 signal gradually shifted from B cells in the germinal center to T cells and macrophages in the interfollicular regions. In the present study, the use of TMA to establish a mathematical model with a wider range of statistical analysis can bring us a step forward to understand the immunopathogenesis of PCV2 infection-associated follicular changes in LNs.

Proposals of statistical consideration to evaluation of results for a specific region in multi-regional trials--Asian perspective.

In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and to shorten approval time, the design of multi-regional trials incorporates subjects from many countries around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. Recently, the trend for simultaneous clinical development in Asian countries being undertaken simultaneously with clinical trials conducted in Europe and the United States has been rapidly rising. In this paper, proposals of statistical consideration to multi-regional trials are provided. More specifically, three aspects are addressed: the definition of the 'Asian region,' the consistency criterion between the 'Asian region' and the overall regions, and the sample size determination for the multi-regional trial.