Influential Periods in Longitudinal Clinical Cardiovascular Health Scores.

The prevalence of ideal cardiovascular health (CVH) among adults in the United States is low and decreases with age. Our objective was to identify specific age windows when the loss of CVH accelerates, to ascertain preventive opportunities for intervention. Data were pooled from 5 longitudinal cohorts (Project Heartbeat!, Cardiovascular Risk in Young Finns Study, The Bogalusa Heart Study, Coronary Artery Risk Development in Young Adults, Special Turku Coronary Risk Factor Intervention Project) from the United States and Finland from 1973 to 2012. Individuals with clinical CVH factors (i.e., body mass index, blood pressure, cholesterol, blood glucose) measured from ages 8 to 55 years were included. These factors were categorized and summed into a clinical CVH score ranging from 0 (worst) to 8 (best). Adjusted, segmented, linear mixed models were used to estimate the change in CVH over time. Among the 18,343 participants, 9,461 (52%) were female and 12,346 (67%) were White. The baseline mean (standard deviation) clinical CVH score was 6.9 (1.2) at an average age of 17.6 (8.1) years. Two inflection points were estimated: at 16.9 years (95% confidence interval: 16.4, 17.4) and at 37.2 years (95% confidence interval: 32.4, 41.9). Late adolescence and early middle age appear to be influential periods during which the loss of CVH accelerates.

Evidence of bias in randomized clinical trials of hepatitis C interferon therapies.

INTRODUCTION: Bias may occur in randomized clinical trials in favor of the new experimental treatment because of unblinded assessment of subjective endpoints or wish bias. Using results from published trials, we analyzed and compared the treatment effect of hepatitis C antiviral interferon therapies experimental or control. METHODS: Meta-regression of trials enrolling naïve hepatitis C virus patients that underwent four therapies including interferon alone or plus ribavirin during past years. The outcome measure was the sustained response evaluated by transaminases and/or hepatitis C virus-RNA serum load. Data on the outcome across therapies were collected according to the assigned arm (experimental or control) and to other trial and patient-level characteristics. RESULTS: The overall difference in efficacy between the same treatment labeled experimental or control had a mean of +11.9% (p < 0.0001). The unadjusted difference favored the experimental therapies of group IFN-1 (+6%) and group IFN-3 (+10%), while there was no difference for group IFN-2 because of success rates from large multinational trials. In a meta-regression model with trial-specific random effects including several trial and patient-level variables, treatment and arm type remained significant (p < 0.0001 and p = 0.0009 respectively) in addition to drug-schedule-related variables. CONCLUSION: Our study indicates the same treatment is more effective when labeled "experimental" compared to when labeled "control" in a setting of trials using an objective endpoint and even after adjusting for patient and study-level characteristics. We discuss several factors related to design and conduct of hepatitis C trials as potential explanations of the bias toward the experimental treatment.

Efficient change point detection for genomic sequences of continuous measurements.

MOTIVATION: Knowing the exact locations of multiple change points in genomic sequences serves several biological needs, for instance when data represent aCGH profiles and it is of interest to identify possibly damaged genes involved in cancer and other diseases. Only a few of the currently available methods deal explicitly with estimation of the number and location of change points, and moreover these methods may be somewhat vulnerable to deviations of model assumptions usually employed. RESULTS: We present a computationally efficient method to obtain estimates of the number and location of the change points. The method is based on a simple transformation of data and it provides results quite robust to model misspecifications. The efficiency of the method guarantees moderate computational times regardless of the series length and the number of change points. AVAILABILITY: The methods described in this article are implemented in the new R package cumSeg available from the Comprehensive R Archive Network at http://CRAN.R-project.org/package=cumSeg.

The relationship between maternal-fetus attachment and perceived parental bonds in pregnant women: Considering a possible mediating role of psychological distress.

Maternal-Fetal Attachment (MFA) delineates the emotional, cognitive, and behavioral aspects that mothers develop toward the unborn baby during pregnancy. The literature indicates that optimal attachment in pregnancy represents a protective factor for the mother-child attachment bond after birth and child development outcomes. To date, there are few studies that have investigated associated factors of MFA. This study sets out to explore the association between perceived parental bonds and maternal-fetal bonding in pregnant women, accounting for factors such as psychological distress, socio-demographic and obstetric characteristics. Methods: In this cross-sectional study, 1,177 pregnant women answered the Parental Bonding Instrument, the Maternal-Fetal Attachment Scale, State-Trait Anxiety Inventory (STAI-Y), and Beck-Depression Inventory (BDI-II). Results: We found out that perceived maternal and paternal care had significant direct effects on maternal-infant bonding during the pregnancy period when controlling for some confounders, including gestational age and mother age among others. Such maternal and paternal perceived care effects were not mediated by levels of psychological distress, which in turn resulted to be a "borderline" significant predictor of prenatal attachment. Interestingly, the gestational age and the mother age emerged to have a significant and synergic nonlinear effect, suggesting the influence on the MFAS of the gestational age depends on the values of the mother age, and likewise, the effect of mother age on MFAS depends on the gestational week. Conclusion: This study expands our knowledge of the intergenerational transmission of attachment pointing out the effects of a woman's perceived bond in relation to her parental figures during the development of the prenatal attachment process. Findings also suggests that parenting support interventions may have benefits that are realized across generations.

Comment on 'Estimating average annual per cent change in trend analysis' by Clegg LX, Hankey BF, Tiwari R, Feuer EJ, Edwards BK, Statistics in Medicine 2009; 28:3670-3682.

We discuss some issues relevant to paper of Clegg and co-authors published in Statistics in Medicine; 28, 3670-3682. Emphasis is on computation of the variance of the sum of products of two estimates, slopes and breakpoints.

A flexible approach to the crossing hazards problem.

We propose a simple and flexible framework for the crossing hazards problem. The method is not confined to two-sample problems, but may also work with continuous exposure variables whose effect changes its sign at some time-point of the observed follow-up time. Penalized partial likelihood estimation relies upon the assumption of a smooth hazard ratio via low-rank basis splines with a conventional difference penalty to ensure smoothness, and additional ad hoc penalties to obtain restricted estimates useful in the context of crossing hazards. The framework naturally also leads to a statistical test that has good power for revealing a global effect under several alternatives, including crossing hazards. We provide the results from a real-data analysis and from some simulations to illustrate empirically the performance of the proposed approach as compared with the possible alternatives.

Modeling temperature effects on mortality: multiple segmented relationships with common break points.

We present a model for estimation of temperature effects on mortality that is able to capture jointly the typical features of every temperature-death relationship, that is, nonlinearity and delayed effect of cold and heat over a few days. Using a segmented approximation along with a doubly penalized spline-based distributed lag parameterization, estimates and relevant standard errors of the cold- and heat-related risks and the heat tolerance are provided. The model is applied to data from Milano, Italy.

Trajectories of Blood Pressure Elevation Preceding Hypertension Onset: An Analysis of the Framingham Heart Study Original Cohort.

Importance: Given that hypertension remains a leading risk factor for chronic disease globally, there are substantial ongoing efforts to define the optimal range of blood pressure (BP). Objective: To identify a common threshold level above which BP rise tends to accelerate in progression toward hypertension. Design, Setting, and Participants: This longitudinal, community-based epidemiological cohort study of adults enrolled in Framingham, Massachusetts, included 1252 participants (mean [SD] age, 35.3 [2.7] years) from the Framingham Original Cohort, of whom 790 (63.1%) were women. Each participant contributed up to 28 serial examinations of standardized resting BP measurements between 1948 and 2005. Exposures: Age and systolic BP. Main Outcomes and Measures: Via a segmented mixed model, we identified significant change points in the association between advancing age and increasing systolic BP among individuals categorized by their age at hypertension onset. Results: Individuals maintained a relatively stable resting systolic BP level prior to hypertension onset. Systolic BP level began to rise at a more rapid rate after reaching a level of 123.2 mm Hg (95% CI, 122.7-130.1 mm Hg) in people with onset at 40 to 49 years; 122.0 mm Hg (95% CI, 120.3-123.9 mm Hg) in those with onset between 50 and 59 years, 124.9 mm Hg (95% CI, 120.2-127.9 mm Hg) in those with onset between 60 and 69 years, and 120.5 mm Hg (95% CI, 118.0-123.2 mm Hg) in those with onset between 70 and 79 years (P = .29 for between-group heterogeneity). Conclusions and Relevance: We observed that individuals in the community generally maintained a systolic BP of less than 120 to 125 mm Hg, above which systolic BP increased at a relatively rapid rate toward overt hypertension. This trend was consistent whether the hypertension manifested earlier or later in life. Thus, a resting systolic BP that chronically exceeds the range of approximately 120 to 125 mm Hg may represent an important threshold of underlying vascular remodeling and signal incipient hypertension irrespective of age. Further investigations are needed to unravel the sequence of hemodynamic and vascular changes occurring prior to hypertension onset.

Animal perception of seasonal thresholds: changes in elephant movement in relation to rainfall patterns.

BACKGROUND: The identification of temporal thresholds or shifts in animal movement informs ecologists of changes in an animal's behaviour, which contributes to an understanding of species' responses in different environments. In African savannas, rainfall, temperature and primary productivity influence the movements of large herbivores and drive changes at different scales. Here, we developed a novel approach to define seasonal shifts in movement behaviour by examining the movements of a highly mobile herbivore (elephant; Loxodonta africana), in relation to local and regional rainfall patterns. METHODOLOGY/PRINCIPAL FINDINGS: We used speed to determine movement changes of between 8 and 14 GPS-collared elephant cows, grouped into five spatial clusters, in Kruger National Park, South Africa. To detect broad-scale patterns of movement, we ran a three-year daily time-series model for each individual (2007-2009). Piecewise regression models provided the best fit for elephant movement, which exhibited a segmented, waveform pattern over time. Major breakpoints in speed occurred at the end of the dry and wet seasons of each year. During the dry season, female elephant are constrained by limited forage and thus the distances they cover are shorter and less variable. Despite the inter-annual variability of rainfall, speed breakpoints were strongly correlated with both local and regional rainfall breakpoints across all three years. Thus, at a multi-year scale, rainfall patterns significantly affect the movements of elephant. The variability of both speed and rainfall breakpoints across different years highlights the need for an objective definition of seasonal boundaries. CONCLUSIONS/SIGNIFICANCE: By using objective criteria to determine behavioural shifts, we identified a biologically meaningful indicator of major changes in animal behaviour in different years. We recommend the use of such criteria, from an animal's perspective, for delineating seasons or other extrinsic shifts in ecological studies, rather than arbitrarily fixed definitions based on convention or common practice.

Segmented relationships to model erosion of regression effect in Cox regression.

In this article we propose a parsimonious parameterisation to model the so-called erosion of the covariate effect in the Cox model, namely a covariate effect approaching to zero as the follow-up time increases. The proposed parameterisation is based on the segmented relationship where proper constraints are set to accomodate for the erosion. Relevant hypothesis testing is discussed. The approach is illustrated on two historical datasets in the survival analysis literature, and some simulation studies are presented to show how the proposed framework leads to a test for a global effect with good power as compared with alternative procedures. Finally, possible generalisations are also presented for future research.

The effect of birthplace on heat tolerance and mortality in Milan, Italy, 1980-1989.

The temperature-mortality relationship follows a well-known J-V shaped pattern with mortality excesses recorded at cold and hot temperatures, and minimum at some optimal value, referred as Minimum Mortality Temperature (MMT). As the MMT, which is used to measure the population heat-tolerance, is higher for people living in warmer places, it has been argued that populations will adapt to temperature changes. We tested this notion by taking advantage of a huge migratory flow that occurred in Italy during the 1950s, when a large number of unemployed people moved from the southern to the industrializing north-western regions. We have analyzed mortality-temperature relationships in Milan residents, split by groups identified by area of birth. In order to obtain estimates of the temperature-related risks, log-linear models have been used to fit daily death count data as a function of different explanatory variables. Results suggest that mortality risks differ by birthplace, regardless of the place of residence, namely heat tolerance in adult life could be modulated by outdoor temperature experienced early in life. This indicates that no complete adaptation might occur with rising external environmental temperatures.

Improvement of wound healing after hemorrhoidectomy: a double-blind, randomized study of botulinum toxin injection.

PURPOSE: Hemorrhoidectomy is usually associated with significant pain during the postoperative period. The spasm of the internal sphincter seems to play an important role in the origin of pain. This study was designed to evaluate the effectiveness of intrasphincter injection of botulinum toxin after hemorrhoidectomy in reducing the maximum resting pressure of the anal canal, accelerating wound healing, and decreasing postoperative pain when resting and during defecation. METHODS: Thirty patients with hemorrhoids of third and fourth degree were included in the study and randomized in two groups. Anorectal manometry was performed preoperatively and 5 and 30 days afterward in all patients undergoing Milligan-Morgan hemorrhoidectomy. One group received an injection of 0.4 ml of saline into the internal anal sphincter, the other group were injected with 0.4 ml of solution containing 20 units of botulinum toxin. RESULTS: After five days from hemorrhoidectomy, maximum resting pressure decreased in the group injected with botulinum toxin and increased in the placebo group. The time of healing and postoperative pain when resting and during defecation significantly decreased in the group treated with an injection of botulinum toxin. CONCLUSIONS: Botulinum toxin injection into internal anal sphincter after hemorrhoidectomy is effective in reducing maximum resting pressure, time of healing, and postoperative pain both on resting and during defecation in absence of complications or side effects.

Estimating regression models with unknown break-points.

This paper deals with fitting piecewise terms in regression models where one or more break-points are true parameters of the model. For estimation, a simple linearization technique is called for, taking advantage of the linear formulation of the problem. As a result, the method is suitable for any regression model with linear predictor and so current software can be used; threshold modelling as function of explanatory variables is also allowed. Differences between the other procedures available are shown and relative merits discussed. Simulations and two examples are presented to illustrate the method.