John J. Chen

The Antibody Response of Pregnant Cameroonian Women to VAR2CSA ID1-ID2a, a Small Recombinant Protein Containing the CSA-Binding Site

In pregnant women, Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women naturally acquire antibodies to ID1-ID2a and if antibodies to ID1-ID2a correlate with absence of placental malaria at delivery. Antibody levels to full-length VAR2CSA and ID1-ID2a were measured in plasma samples from 745 pregnant Cameroonian women, 144 Cameroonian men, and 66 US subjects. IgM levels and IgG avidity to ID1-ID2a were also determined. As expected, antibodies to ID1-ID2a were absent in US controls. Although pregnant Cameroonian women developed increasing levels of antibodies to full-length VAR2CSA during pregnancy, no increase in either IgM or IgG to ID1-ID2a was observed. Surprisingly, no differences in antibody levels to ID1-ID2a were detected between Cameroonian men and pregnant women. For example, in rural settings only 8–9% of males had antibodies to full-length VAR2CSA, but 90–96% had antibodies to ID1-ID2a. In addition, no significant difference in the avidity of IgG to ID1-ID2a was found between pregnant women and Cameroonian men, and no correlation between antibody levels at delivery and absence of placental malaria was found. Thus, the response to ID1-ID2a was not pregnancy specific, but predominantly against cross-reactivity epitopes, which may have been induced by other PfEMP1 antigens, malarial antigens, or microbes. Currently, ID1-ID2a is a leading vaccine candidate, since it binds to the CSA with the same affinity as the full-length molecule and elicits binding-inhibitory antibodies in animals. Further studies are needed to determine if the presence of naturally acquired cross-reactive antibodies in women living in malaria endemic countries will alter the response to ID1-ID2a following vaccination with ID1-ID2a.

Comparison of potentially preventable hospitalizations related to diabetes among Native Hawaiian, Chinese, Filipino, and Japanese elderly compared with whites, Hawai'i, December 2006-December 2010.

Introduction Approximately 25% of individuals aged 65 years or older in the United States have diabetes mellitus. Diabetes rates in this age group are higher for Asian American and Pacific Islanders (AA/PI) than for whites. We examined racial/ethnic differences in diabetes-related potentially preventable hospitalizations (DRPH) among people aged 65 years or older for Japanese, Chinese, Filipinos, Native Hawaiians, and whites. Methods Discharge data for hospitalizations in Hawai‘i for people aged 65 years or older from December 2006 through December 2010 were compared. Annual rates of DRPH by patient were calculated for each racial/ethnic group by sex. Rate ratios (RRs) were calculated relative to whites. Multivariable models controlling for insurer, comorbidity, diabetes prevalence, age, and residence location provided final adjusted rates and RRs. Results A total of 1,815 DRPH were seen from 1,515 unique individuals. Unadjusted RRs for DRPH by patient were less than1 in all AA/PI study groups compared with whites, but were highest among Native Hawaiians and Filipinos. In fully adjusted models accounting for higher diabetes prevalence in AA/PI groups, Native Hawaiian (adjusted rate ratio [aRR] = 1.59), Filipino (aRR = 2.26), and Japanese (aRR = 1.86) men retained significantly higher rates of diabetes-related potentially preventable hospitalizations than whites, as did Filipino women (aRR = 1.61). Conclusion Native Hawaiian, Filipino, and Japanese men and Filipino women aged 65 years or older have a higher risk than whites for DRPH. Health care providers and public health programs for elderly patients should consider effective programs to reduce potentially preventable hospitalizations among Native Hawaiian, Filipino, and Japanese men and Filipino women aged 65 years or older.

Risk-Adjusted In-Hospital Mortality Models for Congestive Heart Failure and Acute Myocardial Infarction: Value of Clinical Laboratory Data and Race/Ethnicity.

OBJECTIVE To examine the impact of key laboratory and race/ethnicity data on the prediction of in-hospital mortality for congestive heart failure (CHF) and acute myocardial infarction (AMI). DATA SOURCES Hawaii adult hospitalizations database between 2009 and 2011, linked to laboratory database. STUDY DESIGN Cross-sectional design was employed to develop risk-adjusted in-hospital mortality models among patients with CHF (n = 5,718) and AMI (n = 5,703). DATA COLLECTION/EXTRACTION METHODS Results of 25 selected laboratory tests were requested from hospitals and laboratories across the state and mapped according to Logical Observation Identifiers Names and Codes standards. The laboratory data were linked to administrative data for each discharge of interest from an all-payer database, and a Master Patient Identifier was used to link patient-level encounter data across hospitals statewide. PRINCIPAL FINDINGS Adding a simple three-level summary measure based on the number of abnormal laboratory data observed to hospital administrative claims data significantly improved the model prediction for inpatient mortality compared with a baseline risk model using administrative data that adjusted only for age, gender, and risk of mortality (determined using 3Ms All Patient Refined Diagnosis Related Groups classification). The addition of race/ethnicity also improved the model. CONCLUSIONS The results of this study support the incorporation of a simple summary measure of laboratory data and race/ethnicity information to improve predictions of in-hospital mortality from CHF and AMI. Laboratory data provide objective evidence of a patients condition and therefore are accurate determinants of a patients risk of mortality. Adding race/ethnicity information helps further explain the differences in in-hospital mortality.

Boundary problem in Simon’s two-stage clinical trial designs

ABSTRACT The activity of a new treatment in clinical trials with binary endpoints can be assessed by comparing the observed response rate to the target response rate. Traditionally, a one-sided hypothesis is used to make statistical inference, and the actual Type I error rate has to be computed over the parameter space of the null hypothesis. The monotonicity property is a fundamental property that guarantees the actual Type I error rate occurring at the boundary. One-arm two-stage designs are considered in this article. We theoretically proved this important property when the final threshold value of a design is less than the first-stage sample size together with another weak condition being satisfied. The method used in this article may finally lead to the final complete proof of this property in the future. We also numerically proved that the monotonicity property is satisfied for designs with the first-stage and the second-stage sample sizes from 10 to 100.

Transcutaneous electrical nerve stimulation for chronic post-herpetic neuralgia

Postherpetic neuralgia remains a therapeutic challenge for the clinician. Many modalities have been utilized with limited success. In this pilot randomized study of patients who were refractory to previous medicinal treatment, the patients were treated with transcutaneous nerve stimulation with a biofeedback capability. After every two treatments with the sham and true device, the patients were required to fill out a standard neuropathic pain scale score. The patients were allowed to select the other device after three consecutive treatments if they felt an inadequate decrease in their pain. The true device was chosen over the sham device by all patients. The majority of these patients treated by the true device reported a statistically significant decrease in pain scores (P < 0.001). Further investigation of this Food and Drug Administration, class 2 accepted, electronic device for relief of pain is warranted for patients with a history of recalcitrant postherpetic neuralgia.

High Rates of Native Hawaiian and Older Japanese Adults Hospitalized with Dementia in Hawai‘i

Data on dementia in Native Hawaiians and many Asian subgroups in the United States are limited. Inpatients with dementia have higher costs, longer stays, and higher mortality than those without dementia. This study compared rates of inpatients with a dementia diagnosis for disaggregated Asian and Pacific Islanders (Native Hawaiian, Chinese, Japanese, Filipino) with those of whites according to age (18–59, 60–69, 70–79, 80–89, ≤90) for all adults hospitalized in Hawai‘i between December 2006 and December 2010; 13,465 inpatients with a dementia diagnosis were identified using International Classification of Diseases, Ninth Revision, codes. Rates were calculated using population size denominators derived from the U.S. Census. In all age categories, Native Hawaiians had the highest unadjusted rates of inpatients with dementia and were more likely to have a dementia diagnosis at discharge at younger ages than other racial and ethnic groups. In adjusted models (controlling for sex, residence location, and insurer), Native Hawaiian inpatients aged 18 to 59 (aRR = 1.50, 95% CI = 0.84–2.69), 60 to 69 (aRR = 2.53, 95% CI = 1.74–3.68), 70 to 79 (aRR = 2.19, 95% CI = 1.78–2.69), and 80 to 89 (aRR = 2.53, 95% CI = 1.24–1.71) were significantly more likely to have dementia than whites, as were Japanese aged 70 to 79 (aRR = 1.30, 95% CI = 1.01–1.67), 80 to 89 (aRR = 1.29, 95% CI = 1.05–1.57), and 90 and older (aRR = 1.51, 95% CI = 1.24–1.85). Japanese aged 18 to 59 had were significantly less likely to have dementia than whites (aRR = 0.40, 95% CI = 0.17–0.94). These patterns have important public health and clinical care implications for Native Hawaiians and older Japanese populations. Future studies should consider whether preventable medical risk, caregiving, socioeconomic conditions, genetic disposition, or a combination of these factors are responsible for these findings.

The Stability of the Monofixation Syndrome

PURPOSE To determine etiology, characteristics, and stability of the monofixation syndrome (MFS) in a chart review of 63 consecutive patients in a private practice of pediatric ophthalmology. DESIGN Retrospective, consecutive chart review. METHODS The charts of 63 consecutive patients with MFS, encountered from 2007-2012 followed for a minimum of 3 years were included. Best visual acuity, motor angle deviation at near, fusion, and stereoacuity as recorded on the most recent visit during the follow-up period were examined. Stability of the MFS was determined by comparing the dates of diagnosis with the last examination for those patients who remained stable. Decompensated patients were also studied for characteristics and results of secondary surgery. RESULTS The etiology of the MFS was esotropia in 58 (92.1%), anisometropia in 2 (3.2%), and exotropia in 3 patients (4.8%). The majority of patients, 57 of 63 (92%), had stable MFS for a mean of 13.9 years. Six esotropic patients decompensated after a mean of 6 years; 5 of these patients were restored to MFS by secondary surgery and 1 spontaneously recovered. Five patients were found to have improved stereoacuity to 60 arc seconds or better by the end of the study. CONCLUSIONS The MFS is a relatively stable binocular status during the first 2 decades of follow-up. A small percentage of patients decompensated, requiring secondary surgery to restore the MFS binocular status. A similar small percentage of MFS patients developed a higher grade of stereoacuity when followed for a sufficient interval of time.

An analytical approach to reduce between-plate variation in multiplex assays that measure antibodies to Plasmodium falciparum antigens

BackgroundAntibodies play an important role in immunity to malaria. Recent studies show that antibodies to multiple antigens, as well as, the overall breadth of the response are associated with protection from malaria. Yet, the variability and reliability of antibody measurements against a combination of malarial antigens using multiplex assays have not been well characterized.MethodsA normalization procedure for reducing between-plate variation using replicates of pooled positive and negative controls was investigated. Sixty test samples (30 from malaria-positive and 30 malaria-negative individuals), together with five pooled positive-controls and two pooled negative-controls, were screened for antibody levels to 9 malarial antigens, including merozoite antigens (AMA1, EBA175, MSP1, MSP2, MSP3, MSP11, Pf41), sporozoite CSP, and pregnancy-associated VAR2CSA. The antibody levels were measured in triplicate on each of 3 plates, and the experiments were replicated on two different days by the same technician. The performance of the proposed normalization procedure was evaluated with the pooled controls for the test samples on both the linear and natural-log scales.ResultsCompared with data on the linear scale, the natural-log transformed data were less skewed and reduced the mean–variance relationship. The proposed normalization procedure using pooled controls on the natural-log scale significantly reduced between-plate variation.ConclusionsFor malaria-related research that measure antibodies to multiple antigens with multiplex assays, the natural-log transformation is recommended for data analysis and use of the normalization procedure with multiple pooled controls can improve the precision of antibody measurements.

Biostatistics Faculty and NIH Awards at U.S. Medical Schools

Statistical principles and methods are critical to the success of biomedical and translational research. However, it is difficult to track and evaluate the monetary value of a biostatistician to a medical school (SoM). Limited published data on this topic are available, especially comparing across SoMs. Using National Institutes of Health (NIH) awards and American Association of Medical Colleges (AAMC) faculty counts data (2010–2013), together with online information on biostatistics faculty from 119 institutions across the country, we demonstrated that the number of biostatistics faculty was significantly positively associated with the amount of NIH awards, both as a school total and on a per faculty basis, across various sizes of U.S. SoMs. Biostatisticians, as a profession, should be proactive in communicating and advocating the value of their work and their unique contribution to the long-term success of a biomedical research enterprise. Supplementary materials for this article are available online.

Epididymal Cysts: Are They Associated With Infertility?

Scrotal sonography is commonly used for evaluation of the infertile male. While epididymal cysts are frequently observed during sonographic assessment, their presence has uncertain import. This study is a retrospective case-control sonographic and chart review comparison of infertile men and fertile volunteers to clarify the possible association of epididymal cysts and infertility. The study included 91 consecutively recruited patients from January 2012 to December 2014. The infertile group consisted patients with male factor infertility who underwent scrotal sonography (n = 67). The fertile group consisted of men requesting vasectomy who were recruited for study involvement and consented to undergo scrotal sonography (n = 24). The main outcome measure was infertility. The existence of epididymal cysts on scrotal sonography was the main risk factor. Predictably, the only sonographic findings associated with infertility were small testes (right: t(df = 89) = −2.52; left: t(df = 89) = −2.28, both p = .01) and the presence of a varicocele, χ2(df = 1) = 5.766 with p = .02. The infertile men were also younger and more likely to use alcohol. Of the 91 men studied, 71% demonstrated epididymal cysts (73% of infertile and 67% of fertile men). Epididymal cysts were not be associated with infertility, χ2(df = 1) = 0.362 with p = .55. This occurrence of epididymal cysts is the highest ever reported (71% of all men). While the occurrence of epididymal cysts in this cohort is unexplained, our observation that these cysts are not associated with infertility will be useful for those clinicians counseling patients observed to have these structures.