Meta-Analysis of the Effect of Excluding Early Deaths on the Estimated Relationship between Body Mass Index and Mortality

ALLISON, DAVID B., MYLES S. FAITH, MOONSEONG HEO, DIANA TOWNSEND-BUTTERWORTH, AND DAVID F. WILLIAMSON. Meta-analysis of the effect of excluding early deaths on the estimated relationship between body mass index and mortality. Obes Res. Objectives: Prospective cohort studies typically observe U-or J-shaped relationships between body mass index (BMI) (kg/m²) and mortality. However, some studies suggest that the elevated mortality at lower BMIs is due to confounding by pre-existing occult disease and recommend eliminating subjects who die during the first several (k) years of follow-up. This meta-analysis tests the effects of such early death exclusion on the BMI-mortality association. Research Methods and Procedures: Studies identified from MEDLINE, review articles, ancestry analyses, and the “invisible college.” Included studies: 1) measured relative body weight at baseline; 2) inchded at least 1000 subjects; 3) reported results with and without early-death exclusion, or relevant data; and 4) did not study exclusively diseased populations. Blank tables were mailed to 131 investigators covering 59 databases. Completed tables (n = 16 databases), electronic raw data (n = 7 databases), and original articles (n = 6 databases) provided final data. Meta-analytic regressions compared the BMI-mortality association with and without early death exclusion. The sample included 29 studies and 1,954,345 subjects. Results: The effect of eliminating early deaths was statistically significant but minuscule in magnitude. Implementation of early death exclusion was estimated to shift the BMI associated with minimum mortality only 0. 4 units for men and 0. 6 units for women at age 50. Even at a BMI 16, the estimated relative risk (compared to BMI 25) decreased only 0. 008 units for men and 0. 076 units for women at age 50. Discussion: Results indicate that either pre-existing disease does not confound the BMI—mortality association or eliminating early deaths is inefficient for reducing that confounding.     

Reduced emotional empathy in adults with subclinical ADHD: evidence from the empathy and systemizing quotient

Studies in children with ADHD suggest impairments in social cognitive functions, whereas studies in adults with ADHD are scarce and inconclusive. The aim of this study was to investigate the relationship between ADHD traits and self-reported social cognitive style in a sample of adults from the general population. For this purpose, a community sample of 685 adults filled out online self-report questionnaires about ADHD symptoms (ADHD Rating Scale, ARS), social cognitive functioning and friendships. The Empathy Quotient (EQ) with the subscales Cognitive Empathy (CE), Emotional Empathy (EE) and Social Skills (SS), and the Systemizing Quotient (SQ) were included for measuring social cognitive style and the Friendship Questionnaire (FQ) for the quality of friendships. Participants who met the DSM-5 criteria on the ARS (‘subclinical ADHD’; n = 56) were compared regarding their social cognitive functioning scores with a control group (n = 56) that was matched for age, sex and student status. With small effect sizes, the subclinical ADHD group showed reduced EE scores on the EQ and a more male social cognitive profile. This result was not influenced by sex or ADHD subtype. This study points to a relationship between traits of ADHD and the emotional aspect of empathy, whereas more complex aspects of empathy were unrelated. These findings should be corroborated in clinical patients with ADHD, employing neuropsychological tests rather than self-report questionnaires.     

A Longitudinal Twin Study of the Direction of Effects between ADHD Symptoms and IQ

While the negative association between ADHD symptoms and IQ is well documented, our knowledge about the direction and aetiology of this association is limited. Here, we examine the association of ADHD symptoms with verbal and performance IQ longitudinally in a population-based sample of twins. In a population-based sample of 4,771 twin pairs, DSM-IV ADHD symptoms were obtained from the Conners’ Parent Rating Scale-Revised. Verbal (vocabulary) and performance (Raven’s Progressive Matrices) IQ were assessed online. ADHD symptom ratings and IQ scores were obtained at ages 12, 14 and 16 years. Making use of the genetic sensitivity and time-ordered nature of our data, we use a cross-lagged model to examine the direction of effects, while modelling the aetiologies of the association between ADHD symptoms with vocabulary and Raven’s scores over time. Although time-specific aetiological influences emerged for each trait at ages 14 and 16 years, the aetiological factors involved in the association between ADHD symptoms and IQ were stable over time. ADHD symptoms and IQ scores significantly predicted each other over time. ADHD symptoms at age 12 years were a significantly stronger predictor of vocabulary and Raven’s scores at age 14 years than vice versa, whereas no differential predictive effects emerged from age 14 to 16 years. The results suggest that ADHD symptoms may put adolescents at risk for decreased IQ scores. Persistent genetic influences seem to underlie the association of ADHD symptoms and IQ over time. Early intervention is likely to be key to reducing ADHD symptoms and the associated risk for lower IQ.     

Combined Psychophysiological Assessment of ADHD: A Pilot Study of Bayesian Probability Approach Illustrated by Appraisal of ADHD in Female College Students

Manifestations of ADHD are observed at both psychological and physiological levels and assessed via various psychometric, EEG, and imaging tests. However, no test is 100% accurate in its assessment of ADHD. This study introduces a stochastic assessment combining psychometric tests with previously reported (Consistency Index) and newly developed (Alpha Blockade Index) EEG-based physiological markers of ADHD. The assessment utilizes classical Bayesian inference to refine after each step the probability of ADHD of each individual. In a pilot study involving six college females with ADHD and six matched controls, the assessment achieved correct classification for all ADHD and non-ADHD participants. In comparison, the classification of ADHD versus non-ADHD participants was < 85% for any one of the tests separately. The procedure significantly improved the score separation between ADHD versus non-ADHD groups. The final average probabilities for ADHD were 76% for the ADHD group and 8% for the control group. These probabilities correlated (r = .87) with the Brown ADD scale and (r = .84) with the ADHD-Symptom Inventory used for the screening of the participants. We conclude that, although each separate test was not completely accurate, a combination of several tests classified correctly all ADHD and all non-ADHD participants. The application of the proposed assessment is not limited to the specific tests used in this study--the assessment represents a general paradigm capable of accommodating a variety of ADHD tests into a single diagnostic assessment.     

K‐Sample Test and Sample Size Calculation for Comparing Slopes in Data with Repeated Measurements

Sample size calculations based on two‐sample comparisons of slopes in repeated measurements have been reported by many investigators. In contrast, the literature has paid relatively little attention to the design and analysis of K‐sample trials in repeated measurements studies where K is 3 or greater. Jung and Ahn (2003) derived a closed sample size formula for two‐sample comparisons of slopes by taking into account the impact of missing data. We extend their method to compare K‐sample slopes in repeated measurement studies using the generalized estimating equation (GEE) approach based on independent working correlation structure. We investigate the performance of the sample size formula since the sample size formula is based on asymptotic theory. The proposed sample size formula is illustrated using a clinical trial example. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Comparisons of phylogenetic hypotheses among different data sets in dwarf dandelions (Krigia,Asteraceae): Additional information from internal transcribed spacer sequences of nuclear ribosomal DNA

The internal transcribed spacer (ITS) region of the 18 S–25 S nuclear ribosomal DNA repeat was sequenced from 19 populations of the tribeLactuceae, including all species of dwarf dandelion (Krigia) and five outgroup genera. The incidence of length changes and base substitutions was at least two times higher for ITS 1 than ITS 2. Interspecific sequence divergence withinKrigia averaged 9.62% (1.61%–15.19%) and 4.26% (0%–6.64%) in ITS 1 and ITS 2, respectively. Intergeneric sequence divergence ranged from 15.6% to 44.5% in ITS 1 and from 8.0% to 28.6% in ITS 2. High sequence divergence and homoplasy among genera of tribeLactuceae suggest that the phylogenetic utility of ITS sequence data is limited to interspecific studies or comparisons among closely related genera. Trees generated from ITS sequences are essentially identical to those from restriction site comparisons of the entire nuclear ribosomal (nr) DNA region. The degree of tree resolution differed depending on how gaps were treated in phylogenetic analyses. The ITS trees were congruent with the chloroplast DNA and morphological phylogenies in three major ways: 1) the sister group relationship betweenKrigia andPyrrhopappus; 2) the recognition of two monophyletic sections,Krigia andCymbia, in genusKrigia; and 3) the monophyly of theK. occidentalis-K. cespitosa clade in sect.Cymbia. However, the two nrDNA-based trees are not congruent with morphology/chloroplast DNA-based trees for the interspecific relationships in sect.Krigia. An average of 22.5% incongruence was observed among fourKrigia data sets. The relatively high degree of incongruence among data sets is due primarily to conflict between trees based on nrDNA and morphological/cpDNA data. The incongruence is probably due to the concerted evolution of nrDNA repeating units. The results fromKrigia and theLactuceae suggest that nrDNA data may have limited utility in phylogenetic studies of plants, especially in groups which exhibit high levels of sequence divergence. Our combined phylogenetic analysis as a total evidence shows the least conflict to each of the individual data sets.     

注意缺损多动障碍和儿茶酚-O-甲基转移酶基因无关联性

以往研究表明,儿茶酚胺系统可能参于注意缺损多动障碍（attention—deficit hyperactivityity disorder,ADHD）的发生,而儿茶酚胺-O-甲基转移酶（catechel—O—methyltransferase,COMT）是一种降解多巴胺和去甲肾上腺素系统的儿茶酚胺神经递质的酶。因此,采用两种以家系为基础的分析方法,即传递不平衡实验（transmission disequilibrium test,TDT）和单倍型为基础的单倍型相对风险率（haplotype—based haplotype relative risk,HHRR）去探讨COMT和中国人群中79个ADHD核心家系的关联性,ADHD诊断符合DSM—IV的诊断标准。TDT（X^2=1．03,df=1,P〉0．05）和HHRR（X^2=1．08,df=1,P〉0．05）两种方法的分析结果表明,COMT等位基因不能优先传递给ADHD儿童,提示在中国人群中ADHD与COMT基因无关联性。     

A psychophysiological marker of attention deficit/hyperactivity disorder (ADHD)--defining the EEG consistency index

This study continues our research to further validate the idea that ADHD (Attention Deficit/Hyperactivity Disorder) interferes with transition from one task to another and this interference can be quantified by a Consistency Index (CI) derived from a specific mathematical representation of EEG data. We reanalyze 32 previously reported data sets present new data for 35 boys and girls, ages 7-12, ADHD or control. Each data set contains EEG, recorded and digitized while participants perform consecutive 10-min tasks: video, reading, and math. For boys, the CI in ADHD was four times lower than in controls, p < .005, for girls this difference was two times, p < .05. ADHD/control classification based on the CI coincided with the DSM-IV criteria for 88% of the boys and for 67% of the girls. Post hoc analysis indicated that the classification utility of the CI diminished with age. A CI below 40% could be a discriminating, reliable, and reproducible marker of ADHD in young boys.     

Parental efficacy and child behavior in a community sample of children with and without attention-deficit hyperactivity disorder (ADHD)

Most studies of attention-deficit hyperactivity disorder (ADHD) youth have obtained data from the perspective of either children or parents, but not both simultaneously. The purpose of this study was to examine child and parent perspectives on parenting in a large community-based sample of children with and without ADHD. We identified children in grades 4?C6 and their parents through surveys administered to a random sample of public schools. We used multivariable logistic regression to determine independent associations between child and parent characteristics and the presence of ADHD while controlling for covariates and clustering by school. Sufficient data were achieved for 2,509 child/parent dyads. Ten percent of youths (n?=?240) had been diagnosed with ADHD. Compared with those without ADHD, those with ADHD were more commonly male (67.9 vs. 48.0?%, p?<?.001) and age 12 or over (16.3 vs. 10.3?%). After adjusting for covariates and clustering, compared to children without ADHD, children with ADHD were significantly more likely to report lower self-regulation (OR?=?0.68, 95?% CI?=?0.53, 0.88) and higher levels of rebelliousness (OR?=?2.00, 95?% CI?=?1.52, 2.69). Compared with parents whose children did not have ADHD, parents of children with ADHD rated their overall parental efficacy substantially lower (OR?=?0.23, 95?% CI?=?0.15, 0.33). However, child assessment of parenting style was similar by ADHD. Despite the internal challenges community-based youth with ADHD face, many parents of ADHD youth exhibit valuable parental skills from the perspective of their children. Feedback of this information to parents may improve parental self-efficacy, which is known to be positively associated with improved ADHD outcomes.     

Age‐discrepant marriages: Cross‐national comparisons of Canadian‐American trends

Abstract

Comparisons of age‐discrepant marriages ideally involve data which are collected at the time of marriage and which are available by single years of age for the same population over time. Although such data are not available for Canadian‐American comparisons, approximations of them are derived from the United States census, from marriage statistics (including statistics for California and for British Columbia), and from selected fortuitous studies of age at marriage. Although available data are not conclusive, they suggest that Canada and the United States do not differ markedly in the incidence of age‐discrepant marriages and that both exhibit longitudinal trends which reflect a decreased incidence of marriages with large husband‐wife age differences and an increased preference for coeval marriages, but exhibit markedly little change in the incidence of wife‐older marriages. Cross‐cultural patterns of age‐discrepant marriages are suggested as an unobtrusive indicator for comparative assessments of the de facto status of women.     

k‐FWER Control without p ‐value Adjustment,with Application to Detection of Genetic Determinants of Multiple Sclerosis in Italian Twins

Summary We show a novel approach for k‐FWER control which does not involve any correction, but only testing the hypotheses along a (possibly data‐driven) order until a suitable number of p‐values are found above the uncorrected α level. p‐values can arise from any linear model in a parametric or nonparametric setting. The approach is not only very simple and computationally undemanding, but also the data‐driven order enhances power when the sample size is small (and also when k and/or the number of tests is large). We illustrate the method on an original study about gene discovery in multiple sclerosis, in which were involved a small number of couples of twins, discordant by disease. The methods are implemented in an R package (someKfwer ), freely available on CRAN.     

Discriminating between ADHD adults and controls using independent ERP components and a support vector machine: a validation study

Background

There are numerous event-related potential (ERP) studies in relation to attention-deficit hyperactivity disorder (ADHD), and a substantial number of ERP correlates of the disorder have been identified. However, most of the studies are limited to group differences in children. Independent component analysis (ICA) separates a set of mixed event-related potentials into a corresponding set of statistically independent source signals, which are likely to represent different functional processes. Using a support vector machine (SVM), a classification method originating from machine learning, this study aimed at investigating the use of such independent ERP components in differentiating adult ADHD patients from non-clinical controls by selecting a most informative feature set. A second aim was to validate the predictive power of the SVM classifier by means of an independent ADHD sample recruited at a different laboratory.

Methods

Two groups of age-matched adults (75 ADHD, 75 controls) performed a visual two stimulus go/no-go task. ERP responses were decomposed into independent components, and a selected set of independent ERP component features was used for SVM classification.

Results

Using a 10-fold cross-validation approach, classification accuracy was 91%. Predictive power of the SVM classifier was verified on the basis of the independent ADHD sample (17 ADHD patients), resulting in a classification accuracy of 94%. The latency and amplitude measures which in combination differentiated best between ADHD patients and non-clinical subjects primarily originated from independent components associated with inhibitory and other executive operations.

Conclusions

This study shows that ERPs can substantially contribute to the diagnosis of ADHD when combined with up-to-date methods.     

A study of the possible association between adenosine A2A receptor gene polymorphisms and attention‐deficit hyperactivity disorder traits

The adenosine A_2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention‐deficit hyperactivity disorder (ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD‐like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population‐based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Attention‐deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms (SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed .     

Prognostic factors of improvement in health-related quality of life in atomoxetine-treated children and adolescents with attention-deficit/hyperactivity disorder,based on a pooled analysis

The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74–1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4–6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99–6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.     

Observational study: Matricaria chamomilla may improve some symptoms of attention-deficit hyperactivity disorder

ObjectiveNoradrenaline and serotonin reuptake inhibitors have been proven to be effective in some cases of ADHD. In this open trial, Matricaria chamomilla, a serotonin and noradrealine reuptake inhibitor, actually used as an antidepressant, has been checked for this indication.MethodThree 14–16-year-old male psychiatric outpatients, diagnosed with attention-deficit disorder (ADHD) have been rated at baseline and while taking Matricaria chamomilla to determine its efficacy as a treatment for ADHD. Improvement was valuated using comparisons of Conners’ parent ratings.ResultsPatients’ mean scores improved for Conners’ hyperactivity, inattention and immaturity factors.ConclusionsAlthough the sample size is very small and therefore generalization is very difficult, this observation indicates that Matricaria chamomilla might be a slightly effective treatment also for ADHD.     

Delayed Sleep Timing and Symptoms in Adults With Attention-Deficit/Hyperactivity Disorder: A Controlled Actigraphy Study

Patients with attention-deficit/hyperactivity disorder (ADHD) often exhibit disrupted sleep and circadian rhythms. Determination of whether sleep disturbance and/or circadian disruption are differentially associated with symptom severity is necessary to guide development of future treatment strategies. Therefore, we measured sleep and ADHD symptoms in participants aged 19–65 who met the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria for ADHD and insomnia without psychiatric comorbidities by monitoring actigraphy and daily sleep logs for 2 wks, as well as the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), the ADHD Rating Scale (ADHD-RS), and a clinic-designed sleep behavior questionnaire. Principal components analysis identified correlated circadian- and sleep-related variables in all participants with ADHD who completed the study (n?=?24). The identified components were entered into a backwards stepwise linear regression analysis, which indicated that delayed sleep timing and increased sleepiness (ESS) (but not sleep duration or sleep efficiency) significantly predicted greater severity of both hyperactive-impulsive and inattentive ADHD symptoms (p <?.05 for partial regression coefficients). In addition, combined subtypes had the most impaired age-adjusted sleep quality (PSQI scores; p?<?.05 compared with healthy controls; n?=?13), and 91.7% of them reported going to bed late due to being “not tired/too keyed up to sleep” compared with 57.2% and 50% of inattentive and symptom-controlled participants, respectively (p?<?.05). In conclusion, the results of this study suggest that ADHD symptom severity correlates with delayed sleep timing and daytime sleepiness, suggesting that treatment interventions aimed at advancing circadian phase may improve daytime sleepiness. In addition, ADHD adults with combined hyperactive-impulsive and inattentive symptoms have decreased sleep quality as well as the delayed sleep timing of predominately inattentive subtypes. (Author correspondence: rfargason@uab.edu)     

Analytical partitioning of poly(ethylene glycol)-modified proteins

Covalently grafting proteins with varying numbers (n) of poly(ethylene glycol) molecules (PEGs) often enhances their biomedical and industrial usefulness. Partition between the phases in aqueous polymer two-phase systems can be used to rapidly characterize polymer-protein conjugates in a manner related to various enhancements. The logarithm of the partition coefficient (K) approximates linearity over the range 0<n<x. However, x varies with the nature of the conjugate (e.g., protein molecular mass) and such data analysis does not facilitate the comparison of varied conjugates. The known behavior of surface localized PEGs suggests a better correlation should exist between log K and the weight fraction of polymer in PEG-protein conjugates. Data from four independent studies involving three proteins (granulocyte-macrophage colony stimulation factor, bovine serum albumin and immunoglobulin G) has been found to support this hypothesis. Although somewhat simplistic, ‘weight fraction’ based analysis of partition data appears robust enough to accommodate laboratory to laboratory variation in protein, polymer and phase system type. It also facilitates comparisons between partition data involving disparate polymer-protein conjugates.     

Diurnal Variation in Temperature,Mental and Physical Performance,and Tasks Specifically Related to Football (Soccer)

Football (soccer) training and matches are scheduled at different times throughout the day. Association football involves a variety of fitness components as well as psychomotor and game‐related cognitive skills. The purpose of the present research, consisting of two separate studies, was to determine whether game‐related skills varied with time of day in phase with global markers of both performance and the body clock. In the first study, eight diurnally active male association football players (19.1±1.9 yrs of age; mean±SD) with 10.8±2.1 yrs playing experience participated. Measurements were made on different days at 08:00, 12:00, 16:00, and 20:00 h in a counterbalanced manner. Time‐of‐day changes in intra‐aural temperature (used as a marker of the body clock), grip strength, reaction times, flexibility (markers of aspects of performance), juggling and dribbling tasks, and wall‐volley test (football‐specific skills) were compared. Significant (repeated measures analysis of variance, ANOVA) diurnal variations were found for body temperature (p<0.0005), choice reaction time (p<0.05), self‐rated alertness (p<0.0005), fatigue (p<0.05), forward (sit‐and‐reach) flexibility (p<0.02), and right-hand grip strength (p<0.02), but not left-hand grip strength (p=0.40) nor whole‐body (stand‐and‐reach) flexibility (p=0.07). Alertness was highest and fatigue lowest at 20:00 h. Football‐specific skills of juggling performance showed significant diurnal variation (p<0.05, peak at 16:00 h), whereas performance on the wall‐volley test tended to peak at 20:00 h and dribbling showed no time‐of‐day effect (p=0.55). In a second study, eight diurnally active subjects (23.0±0.7 yrs of age) completed five test sessions, at the same times as in the first study but with a second session at 08:00 h. Test‐re‐test comparisons at 08:00 h for all components indicated good reliability. Intra‐aural temperature showed a significant time‐of‐day effect (p<0.001) with mean temperature at 16:00 h (36.4°C) higher than at 08:00 h (35.4°C). There was no significant effect of chronotype on the temperature acrophase (peak time) (p>0.05). Diurnal variation was found for performance tests, including sit‐and‐reach flexibility (p<0.01) and spinal hyper‐extension (p<0.05). Peaks occurred between 16:00 and 20:00 h and the daytime changes paralleled the temperature rhythm. Diurnal variation was also found for football‐specific tests, including dribbling time (p<0.001, peak at 20:00 h) and chip test performance (p<0.01), being more accurate at 16:00 h (mean error=0.75 m) than at 08:00 h (mean error=1.01 m). Results indicate football players perform at an optimum between 16:00 and 20:00 h when not only football‐specific skills but also measures of physical performance are at their peak. Body temperature peaked at a similar time, but positive mood states seemed to peak slightly earlier. While causal links cannot be established in these experiments, the results indicate that the diurnal variation of some aspects of football performance is affected by factor(s) other than body temperature alone.