Distribution of odds ratio in 2 × 2 contingency table: adjustment for correlation

The Log-odds ratio for 2 × 2 contingency tables is often approximated by a normal distribution with an approximated variance. Hwang and Biswas (2008) illustrated that the standard expression for the variance should be modified in the presence of correlation. They also provided an adjustment to this variance expression when a single 2 × 2 table is available with matched-pair data. In this present paper, we first provide the required adjustment for multiple 2 × 2 tables, theoretically and also with reference to some data examples. We illustrate that this variance-adjusted normal approximation is a better approximation for such data. We provide two examples, one of which came from a late-phase clinical trial. As the theoretical development of this research depends on the existence of a bivariate binomial distribution, a multivariate (and hence bivariate) binomial distribution is motivated and derived. We then provide a suitably correlation adjusted Mantel-Haenszel test procedure.     

Cardiovascular effects of nickel in ambient air

BACKGROUND: Fine particulate matter (FPM) in ambient air causes premature mortality due to cardiac disease in susceptible populations. OBJECTIVE: Our objective in this study was to determine the most influential FPM components. METHODS: A mouse model of atherosclerosis (ApoE-/-) was exposed to either filtered air or concentrated FPM (CAPs) in Tuxedo, New York (85 microg/m3 average, 6 hr/day, 5 days/week, for 6 months), and the FPM elemental composition was determined for each day. We also examined associations between PM components and mortality for two population studies: National Mortality and Morbidity Air Pollution Study (NMMAPS) and Hong Kong. RESULTS: For the CAPs-exposed mice, the average of nickel was 43 ng/m3, but on 14 days, there were Ni peaks at approximately 175 ng/m3 and unusually low FPM and vanadium. For those days, back-trajectory analyses identified a remote Ni point source. Electrocardiographic measurements on CAPs-exposed and sham-exposed mice showed Ni to be significantly associated with acute changes in heart rate and its variability. In NMMAPS, daily mortality rates in the 60 cities with recent speciation data were significantly associated with average Ni and V, but not with other measured species. Also, the Hong Kong sulfur intervention produced sharp drops in sulfur dioxide, Ni, and V, but not other components, corresponding to the intervention-related reduction in cardiovascular and pulmonary mortality. CONCLUSIONS: Known biological mechanisms cannot account for the significant associations between Ni with the acute cardiac function changes in the mice or with cardiovascular mortality in people at low ambient air concentrations; therefore, further research is needed.     

Effects of Concentrated Ambient Particles on Heart Rate,Blood Pressure,and Cardiac Contractility in Spontaneously Hypertensive Rats

Epidemiological studies have shown that particulate matter (PM) air pollution is associated with cardiovascular mortality and morbidity, especially for particles with aerodynamic diameters under 2.5 μm (PM_2.5). Recent studies have revealed an association between PM pollution and autonomic functions including heart rate (HR), blood pressure (BP), and heart-rate variability. However, the association and linking mechanisms have not been clearly demonstrated in animal studies. Utilizing a novel approach that employs a mixed-effects model to overcome the problems of variations in diseased animals and circadian cycles, we have previously demonstrated an association between concentrated PM_2.5 and changes of HR and BP in pulmonary hypertensive rats. The objective of this study is to test the plausibility of this methodology and to demonstrate the particle effects under different pathophysiology. The feasibility of cardiac contractility (measured as QA interval, QAI) as an indicator for PM toxicology was also explored. Four spontaneously hypertensive (SH) rats were repeatedly exposed to concentrated PM_2.5 during spring and summer. The mass concentration of particles during the 5 h of exposure was 202.0 ± 68.8 (mean ± SE) and 141.0 ± 54.9 μg/m³ for spring and summer experiments, respectively. During spring exposures, the maximum increase of HR and mean BP noted at the end of exposure were 51.6 bpm (p < .001) and 8.7 mm Hg (p = .002), respectively. The maximum decrease of QAI noted at the same time was 1.6 ms (p = .001). Though a similar pattern was demonstrated during summer exposures, the responses were less prominent. We conclude that concentrated PM_2.5 may increase HR and mean BP and decrease QAI in SH rats. Our results also show that QAI may be used as an indicator in PM toxicology.     

Integrating health profile with survival for quality of life assessment

In cohort studies or clinical trials, measurements of quality of life (QoL) were averaged across available individuals for each group at given points in time to produce single measures for comparisons. However, estimates of these single measures may be severely biased if substantial mortality occurs over time. The objective of this study is to develop a method that integrates QoL measurement and survival for long-term evaluation of health services. We defined a mean QoL score function over time for an index population as the average QoL score of all individuals both alive and dead at each time point in the population. While a living subject's QoL can be assessed by asking one's subjective preference, the score of a decedent can be assigned a fixed value depending on the specific facet on health profile. The mean QoL score function over time is reduced to a single measure of expected cumulative QoL score, which is the area under the curve of mean QoL score function over a given time interval and can be estimated by taking a random sample from a cross-sectional survey. For the QoL score function to be extrapolated to life-long, it requires the assumption that the disease causes premature death or a long-term moderate impairment of QoL. We provided methods and computer programs for estimating mean QoL score functions and the reduced single measures for use in comparisons. A cohort of 779 breast cancer patients from Chiangmai, Thailand were followed for 12 years to demonstrate the proposed methods. The data included the 12-year complete survival records and QoL scores on 233 patients collected from a cross-sectional survey using WHOQOL questionnaire and standard gamble method. The expected cumulative QoL scores using utility and psychometric scales were compared among patients in four groups of clinical stages in this cohort for time from onset up to 12 years and life-long. We conclude that such an integration of QoL measurement with survival can be useful for the evaluation of health service and clinical decision.     

Effects of concentrated ambient particles on heart rate, blood pressure, and cardiac contractility in spontaneously hypertensive rats during a dust storm event

Epidemiological studies have suggested that cardiovascular mortality and morbidity increased during Asian dust events. The findings were still inconclusive though. We have shown an increased pulmonary toxicity in diseased animals during a dust storm event. However, the toxicity nature of dust storm particles remains unclear. It is our objective in this study to further investigate the cardiovascular effects of concentrated PM(2.5) on spontaneously hypertensive rats during the same dust storm event. Four spontaneously hypertensive rats were implanted with radiotelemetry transmitters at the age of 10 wk. Baseline heart rate, mean blood pressure, and cardiac contractility (measured as QA interval, QAI) data were collected 4 wk before. Exposure group received concentrated ambient particles inhalation for 6 h during a dust storm event, while the control group received room air inhalation at the same time. Self-control data were collected 4 wk after the event during the same clock hours while there was no dust storm. Gravimetric analysis showed a particle mass concentration of 315.55 microg/m(3) during the 6 h of exposure. A linear mixed-effects model revealed sigmoid increases in heart rate (to a maximum of 93.8 +/- 18.8 bpm) and mean blood pressure (to a maximum of 14.8 +/- 5.4 mm Hg), and a sigmoid decrease of QAI (to a maximum of - 3.5 +/- 1.5 ms) during the exposure after an initial incubation period. We conclude that concentrated dust storm particles, which are different from products of automobile combustion process, may cause adverse cardiovascular effects on diseased animals.     

An index related to the autocorrelation function of RR intervals for the analysis of heart rate variability

Heart rate variability (HRV) is concerned with analysis of the variations in the intervals between heartbeats, known as RR intervals. Commonly used HRV indices may be insensitive in detecting some dynamic changes related to complex autocorrelation functions of the RR intervals. For example, indices SD1 and SD2 of the Poincaré plot can be expressed by the variance and first auto-covariance of the signal. The acceleration change index is related to the autocorrelation functions of the series only at the first three lags. We extend the idea of characterizing the sign of differences of a time series to propose a new index called VRL, which is the variance of the run length of the sign of the lagged differentiated time series. The theoretical study shows that VRL is directly related to the autocorrelation functions of the RR series at larger lags. Simulated data are used to validate the theoretical results and assess the power of testing group differences measured with VRL and other HRV indices. The performance of VRL is also evaluated for classifying subjects with normal sinus rhythm and congestive heart failure using the RR intervals taken from the PhysioNet database. We apply the index to RR intervals from an animal study of long-term exposure to particulate matter. The VRL values for the young mice susceptible to atherosclerosis in the control and exposure groups decreased gradually with different slopes after several weeks of exposure. The exposure effect changes in this HRV index estimated by fitting a generalized additive model are significant after 7 weeks of exposure.     

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. III. Acute and chronic effects of CAPs on heart rate, heart-rate fluctuation, and body temperature

Normal mice (C57) and mice prone to develop atherosclerosis (ApoE-/-) were implanted with electrocardiograph (EKG), core body temperature, and motion transmitters were exposed daily for 6 h to Tuxedo, NY, concentrated ambient particles (CAPs) for 5 day/wk during the spring and summer of 2003. The series of 5-min EKG monitoring and body-temperature measurements were obtained for each animal in the CAPs and filtered air sham exposure groups. Our hypothesis was that chronic exposure could cause cumulative health effects. We used our recently developed nonparametric method to estimate the daily time periods that mean heart rates (HR), body temperature, and physical activity differed significantly between the CAPs and sham exposed group. CAPs exposure most affected heart rate between 1:30 a.m. and 4:30 a.m. With the response variables being the average heart rate, body temperature, and physical activity, we adopted a two-stage modeling approach to obtain the estimates of chronic and acute effects on the changes of these three response variables. In the first stage, a time-varying model estimated daily crude effects. In the second stage, the true means of the estimated crude effects were modeled with a polynominal function of time for chronic effects, a linear term of daily CAPs exposure concentrations for acute effects, and a random component for unknown noise. A Bayesian framework combined these two stages. There were significant decreasing patterns of HR, body temperature, and physical activity for the ApoE-/- mice over the 5 mo of CAPs exposure, with smaller and nonsignificant changes for the C57 mice. The chronic effect changes of the three response variables for ApoE-/- mice were maximal in the last few weeks. There was also a significant relationship between CAPs exposure concentration and short-term changes of heart rate in ApoE-/- mice during exposure. Response variables were also defined for examining fluctuations of 5-min heart rates within long (i.e., 3-6 h) and short time periods (i.e., approximately 15 min). The results for the ApoE-/- mice showed that heart-rate fluctuation within the longer periods increased to 1.35-fold by the end of exposure experiment, while the heart-rate fluctuation within 15 min decreased to 0.7-fold.     

Finished herbal product as an alternative treatment for menopausal symptoms in climacteric women

BACKGROUND: There is a paucity of scientific evidence supporting the efficacy of herbal medicines in treating menopausal symptoms. OBJECTIVE: The aim of this study was to evaluate safety and efficacy of the finished herbal product TMN-1 in the treatment of menopausal symptoms in climacteric women. DESIGN AND SETTING: A multicenter, prospective, observational follow-up study was conducted from July 2003 to December 2004 in four hospitals in Taiwan. PARTICIPANTS: Initially, 126 women were included who were between 45 and 55 years of age, were experiencing hot flashes, and were without hormone replacement therapy. Women were excluded if they had any signs of active cancer. Of the participants, 82% completed the study. The reasons for withdrawal included adverse effects (n = 7), failed to return (n = 7), lack of efficacy (n = 6), and from protocol deviation (n = 3). INTERVENTION: Every participant received TMN-1 treatment 4 g, 3 times per day, for 12 weeks. MAIN OUTCOME MEASURE: Primary measures were change in frequency of hot flashes and severity of menopausal symptoms measured by Kupperman Index (KI). Secondary outcomes included changes in quality of life and adverse events. RESULTS: Significant improvement in scores of hot flashes and KI were found at weeks 4 and 12 in the 50 peri- and 53 postmenopausal women who completed this study (p < 0.001). Logistic regression analyses showed that perimenopausal women with hot flashes had sevenfold (95% confidence interval [CI], 1.8-28.0) odds of improvement in favor of treatment, whereas that of the postmenopausal group was 1.5 (95% CI, 0.5 to 4.2). Further analyses showed that TMN-1 produced superior benefit in women with moderate and severe menopausal symptoms (KI > or = 21), compared to those with mild symptoms. It also improved symptoms of insomnia, nervousness, melancholia, and palpitation in perimenopausal women. Five (5) adverse drug reactions were detected: three single events of nausea, abdominal pain, and abdominal fullness; and two events of diarrhea. CONCLUSIONS: This study provides evidence that 12 weeks of TMN-1 therapy is a viable alternative treatment to consider in perimenopausal women with hot flashes, particularly in those with palpitations, emotional disturbance, and insomnia.     

Cost-effectiveness of highly active antiretroviral therapy for HIV infection in Taiwan.

BACKGROUND/PURPOSE: Since the late 1980s, the Taiwanese government has provided all HIV-infected citizens with free access to antiretroviral therapy. Recently, there is controversy as to whether or not free access to expensive highly active antiretroviral therapy (HAART) should be continued for HIV-infected patients. This study aimed to evaluate the cost-effectiveness of HAART therapy. METHODS: HAART-associated improvement in survival was obtained by analyzing the follow-up data of all HIV-positive patients identified during April 1984 to March 1997 (pre-HAART era) and May 1997 to April 2003 (HAART era) in Taiwan. Data on quality of life in HIV-positive patients was obtained from a cross-sectional survey of 224 patients using standard gamble method and World Health Organization Quality of Life-BREF instrument. Information regarding the cost of HAART was obtained from the National Health Insurance (NHI). RESULTS: In 2000, the average annual NHI expenditure on HAART per HIV-positive patient receiving HAART was NT$210,018 (US$6177, at an exchange rate of 34.0 NT$/US$). In the AIDS group, the cost was NT$176,441 (US$5189) per life year gained and NT$241,700 (US$7109) per quality-adjusted life year gained. For non-AIDS patients, the corresponding costs were NT$226,156 (US$6652) and NT$332,582 (US$9782), respectively. These estimates have not yet included the additional cost savings from HAART-associated reduction in hospitalization and use of antimicrobial agents for opportunistic infections, and the additional life years gained from the reduction in HIV transmission under the universal availability of HAART. CONCLUSION: HAART for HIV infection is cost-effective, especially when the societal and epidemiologic factors are considered. We recommend that the policy of providing free HAART to all HIV-infected citizens be continued.