Biomedical subjects

John R Thompson

Publications and source records attributed to John R Thompson.

At least 19 recordsLinked to original sources

PubMed2007

Evidence-based sample size calculations based upon updated meta-analysis.

Meta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence regarding the effectiveness of interventions and as such underpin much of evidence-based medicine. Despite this, meta-analyses are usually produced as observational by-products of the existing literature, with no formal consideration of future meta-analyses when individual trials are being designed. Basing the sample size of a new trial on the results of an updated meta-analysis which will include it, may sometimes make more sense than powering the trial in isolation. A framework for sample size calculation for a future RCT based on the results of a meta-analysis of the existing evidence is presented. Both fixed and random effect approaches are explored through an example. Bayesian Markov Chain Monte Carlo simulation modelling is used for the random effects model since it has computational advantages over the classical approach. Several criteria on which to base inference and hence power are considered. The prior expectation of the power is averaged over the prior distribution for the unknown true treatment effect. An extension to the framework allowing for consideration of the design for a series of new trials is also presented. Results suggest that power can be highly dependent on the statistical model used to meta-analyse the data and even very large studies may have little impact on a meta-analysis when there is considerable between study heterogeneity. This raises issues regarding the appropriateness of the use of random effect models when designing and drawing inferences across a series of studies.

Anti-Bacterial Agents↗

PubMed2007

Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study.

BACKGROUND: Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease. METHODS: We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS. FINDINGS: Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest). INTERPRETATION: Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.

Aging↗

PubMed2007

Bivariate random-effects meta-analysis and the estimation of between-study correlation.

BACKGROUND: When multiple endpoints are of interest in evidence synthesis, a multivariate meta-analysis can jointly synthesise those endpoints and utilise their correlation. A multivariate random-effects meta-analysis must incorporate and estimate the between-study correlation (rhoB). METHODS: In this paper we assess maximum likelihood estimation of a general normal model and a generalised model for bivariate random-effects meta-analysis (BRMA). We consider two applied examples, one involving a diagnostic marker and the other a surrogate outcome. These motivate a simulation study where estimation properties from BRMA are compared with those from two separate univariate random-effects meta-analyses (URMAs), the traditional approach. RESULTS: The normal BRMA model estimates rhoB as -1 in both applied examples. Analytically we show this is due to the maximum likelihood estimator sensibly truncating the between-study covariance matrix on the boundary of its parameter space. Our simulations reveal this commonly occurs when the number of studies is small or the within-study variation is relatively large; it also causes upwardly biased between-study variance estimates, which are inflated to compensate for the restriction on rhoB. Importantly, this does not induce any systematic bias in the pooled estimates and produces conservative standard errors and mean-square errors. Furthermore, the normal BRMA is preferable to two normal URMAs; the mean-square error and standard error of pooled estimates is generally smaller in the BRMA, especially given data missing at random. For meta-analysis of proportions we then show that a generalised BRMA model is better still. This correctly uses a binomial rather than normal distribution, and produces better estimates than the normal BRMA and also two generalised URMAs; however the model may sometimes not converge due to difficulties estimating rhoB. CONCLUSION: A BRMA model offers numerous advantages over separate univariate synthesises; this paper highlights some of these benefits in both a normal and generalised modelling framework, and examines the estimation of between-study correlation to aid practitioners.

CD4 Lymphocyte Count↗

PubMed2006

Using pseudo-data to correct for publication bias in meta-analysis.

In many ways, adjustment for publication bias in meta-analysis parallels adjustment for ascertainment bias in genetic studies. We investigate a previously published simulation-based method for dealing with complex ascertainment bias and show that it can be modified for use in meta-analysis when publication bias is suspected. The method involves simulating sets of pseudo-data under the assumed model using guesses for the unknown parameters. The pseudo-data are subjected to the same selection criteria as are believed to have operated on the original data. A conditional likelihood is then used to estimate the adjusted values of the unknown parameters. This method is used to re-analyse a published meta-analysis of the effect of the MTHFR gene on homocysteine levels. Simulation studies show that the pseudo-data method is unbiased; they give an indication of the number of pseudo-data values required and suggest that a two-stage adjustment produces less variable estimates. This method can be thought of as an example of the selection model approach to publication bias correction. As the selection mechanism must be assumed, it is important to investigate the sensitivity of any conclusions to this assumption.

Cardiovascular Diseases↗

PubMed2006

Serious complications of local anaesthesia for cataract surgery: a 1 year national survey in the United Kingdom.

BACKGROUND: The techniques of sub-Tenon's, topical and topical-intracameral local anaesthesia (LA) have become common in routine practice. AIMS: This study aimed (i) to estimate the frequency of various LA techniques used in cataract surgery, (ii) to estimate the incidence of severe adverse events associated with each LA technique, and (iii) to document these adverse events. METHODS: This was a prospective, 13 month observational study of routine practice in the UK in 2002-2003. The British Ophthalmological Surveillance Unit sent a monthly mailing to UK ophthalmologists, asking for reports of "potentially sight-threatening or life-threatening complications of LA for cataract surgery". Current LA practice was assessed by questionnaire. RESULTS: Cataract surgery comprised 4.1% general anaesthesia, 92.1% LA without sedation and 3.9% LA with sedation. Of the estimated 375 000 LAs 30.6% were peribulbar, 3.5% retrobulbar, 42.6% sub-Tenon's, 1.7% sub-conjunctival, 9.9% topical and 11.0% topical-intracameral LA. "Potentially sight-threatening complications" were mostly associated with retrobulbar and peribulbar techniques and "potentially life-threatening" complications with all techniques except topical/intracameral LA. Eight neurological complications consistent with brainstem anaesthesia were reported: 7 with peribulbar or retrobulbar LA. Poisson regression analysis strongly indicated that rates vary with technique (p<0.001 for "potentially sight-threatening" complications, p = 0.03 for "neurological" complications). Because of likely under-reporting, further complications probably occurred during the survey period. CONCLUSIONS: This large survey found a lower rate of reported serious complications with sub-Tenon's, topical and topical-intracameral LA compared with retrobulbar and peribulbar techniques. These "newer" methods may be preferable for routine cataract surgery.

Anesthesia, Local↗

PubMed2006

LGALS2 functional variant rs7291467 is not associated with susceptibility to myocardial infarction in Caucasians.

Myocardial infarction (MI) is currently among the leading causes of death in the developed world. A functional SNP (rs7291467) in galectin-2 (LGALS2), a protein involved in the LTA cascade, has been associated with susceptibility to MI in the Japanese population. We explored for the first time the hypothesis that the same SNP could be associated with the risk of MI in the British population. We conducted a case-control association study on a cohort of 752 British MI patients and 705 population controls. Power calculations showed that our resource had 98% of power to detect a significant association at OR of 1.57, and 80% power to detect an association with an OR of 1.35 (recessive model). Despite this, we found no significant association of allele frequency with risk of MI. Stratification for age, gender and other cardiovascular risk factors also failed to reveal an association of this polymorphism with MI.

Adult↗

PubMed2006

Estimating and modeling the cure fraction in population-based cancer survival analysis.

In population-based cancer studies, cure is said to occur when the mortality (hazard) rate in the diseased group of individuals returns to the same level as that expected in the general population. The cure fraction (the proportion of patients cured of disease) is of interest to patients and is a useful measure to monitor trends in survival of curable disease. There are 2 main types of cure fraction model, the mixture cure fraction model and the non-mixture cure fraction model, with most previous work concentrating on the mixture cure fraction model. In this paper, we extend the parametric non-mixture cure fraction model to incorporate background mortality, thus providing estimates of the cure fraction in population-based cancer studies. We compare the estimates of relative survival and the cure fraction between the 2 types of model and also investigate the importance of modeling the ancillary parameters in the selected parametric distribution for both types of model.

Aged↗

PubMed2006

The VF-14 and psychological impact of amblyopia and strabismus.

PURPOSE: To assess the impact of amblyopia, strabismus and glasses on subjective visual and psychological function among amblyopes. METHODS: Questionnaires were administered to 120 teenagers with amblyopia (cases), with residual amblyopia after treatment, or with or without strabismus and 120 control subjects (controls) Cases underwent ophthalmic examination including cycloplegic refraction. Two questionnaires (visual function 14 [VF-14] and a newly designed eight-item questionnaire) were administered to assess the psychological impact score of general daily life, having a weaker eye, glasses wear, and current noticeable strabismus. Questionnaires were validated in 60 subjects in each group by a second administration of the questionnaire. The VF-14 scores, psychological impact scores, and clinical data were compared. RESULTS: The VF-14 and psychological impact scores were highly reproducible. The mean VF-14 score for the control group was 95.5 and for the cases was 78.9 (P < 0.0001), but the scores did not correlate with the severity of amblyopia. The psychological impact score in general daily life was sensitive in discriminating between mild (median score 31) and moderate to severe (median score 56) amblyopes (P < 0.02). The cases segregated into two clear groups; those who scored high (large detrimental psychological impact) on psychological impact, with subjectively noticeable manifest strabismus, and those who scored low (low detrimental psychological impact), without noticeable strabismus. The subjective experience of patching treatment differentiated the two groups best of all. CONCLUSIONS: Subjective visual and psychological functions are altered compared with normal subjects due to amblyopia, strabismus, and a previous unpleasant patching experience. The mean VF-14 score was similar to that previously published for patients with glaucoma. The study underlines that amblyopia and/or strabismus have an impact on teenagers' subjective visual function and well-being.

Activities of Daily Living↗

PubMed2005

Bayesian implementation of a genetic model-free approach to the meta-analysis of genetic association studies.

A genetic model-free method for the meta-analysis of genetic association studies is described that estimates the mode of inheritance from the data rather than assuming that it is known. For a bi-allelic polymorphism, with G as risk allele and g as wild-type, the genetic model depends on the ratio of the two log odds ratios, lambda = log OR(Gg)/log OR(GG), where OR(GG) compares GG with gg and OR(Gg) compares Gg with gg. Modelling log OR(GG) as a random effect creates a hierarchical model that can be implemented within a Bayesian framework. In Bayesian modelling, vague prior distributions have to be specified for all unknown parameters when no external information is available. When the data are sparse even supposedly vague prior distributions may have an influence on the posterior estimates. We investigate the impact of different vague prior distributions for the between-study standard deviation of log OR(GG) and for lambda, by considering three published meta-analyses and associated simulations. Our results show that depending on the characteristics of the meta-analysis the results may indeed be sensitive to the choice of vague prior distribution for either parameter. Genetic association studies usually use a case-control design that should be analysed by the corresponding retrospective likelihood. However, under some circumstances the prospective likelihood has been shown to produce identical results and it is usually preferred for its simplicity. In our meta-analyses the two likelihoods give very similar results.

Bayes Theorem↗

PubMed2005

The choice of a genetic model in the meta-analysis of molecular association studies.

BACKGROUND: To evaluate gene-disease associations, genetic epidemiologists collect information on the disease risk in subjects with different genotypes (for a bi-allelic polymorphism: gg, Gg, GG). Meta-analyses of such studies usually reduce the problem to a single comparison, either by performing two separate pairwise comparisons or by assuming a specific underlying genetic model (recessive, co-dominant, dominant). A biological justification for the choice of the genetic model is seldom available. METHODS: We present a genetic model-free approach, which does not assume that the underlying genetic model is known in advance but still makes use of the information available on all genotypes. The approach uses OR(GG), the odds ratio between the homozygous genotypes, to capture the magnitude of the genetic effect, and lambda, the heterozygote log odds ratio as a proportion of the homozygote log odds ratio, to capture the genetic mode of inheritance. The analysis assumes that the same unknown genetic model, i.e. the same lambda, applies in all studies, and this is investigated graphically. The approach is illustrated using five examples of published meta-analyses. RESULTS: Analyses based on specific genetic models can produce misleading estimates of the odds ratios when an inappropriate model is assumed. The genetic model-free approach gives appropriately wider confidence intervals than genetic model-based analyses because it allows for uncertainty about the genetic model. In terms of assessment of model fit, it performs at least as well as a bivariate pairwise analysis in our examples. CONCLUSIONS: The genetic model-free approach offers a unified approach that efficiently estimates the genetic effect and the underlying genetic model. A bivariate pairwise analysis should be used if the assumption of a common genetic model across studies is in doubt.

Cardiovascular Diseases↗

PubMed2005

Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.

In traditional epidemiological studies the association between phenotype (risk factor) and disease is often biased by confounding and reverse causation. As a person's genotype is assigned by a seemingly random process, genes are potentially useful instrumental variables for adjusting for such bias. This type of adjustment combines information on the genotype-disease association and the genotype-phenotype association to estimate the phenotype-disease association and has become known as Mendelian randomization. The information on genotype-disease and genotype-phenotype may well come from a meta-analysis. In such a synthesis, a multivariate approach needs to be used whenever some studies provide evidence on both the genotype-phenotype and genotype-disease associations. This paper presents two multivariate meta-analytical models, which differ in their treatment of the heterogeneities (between-study variances). Heterogeneities on the genotype-phenotype and genotype-disease associations may be highly correlated, but a multivariate model that parameterizes the heterogeneity directly is difficult to fit because that correlation is poorly estimated. We advocate an alternative model that treats the heterogeneities on genotype-phenotype and phenotype-disease as being independent. This model fits readily and implicitly defines the correlation between the heterogeneities on genotype-phenotype and genotype-disease. We show how either maximum likelihood or a Bayesian approach with vague prior distributions can be used to fit the alternative model.

Coronary Disease↗

PubMed2005

Quantitative histomorphometric analysis of gonadal steroid receptor distribution in the normal human endometrium through the menstrual cycle.

The aim of this study was to test the hypothesis that the distribution of oestrogen receptor beta (ERbeta) and androgen receptor (AR) are related to cell proliferation or correlated with the expression of progesterone receptor (PR) or oestrogen receptor alpha (ERalpha) in the normal human endometrium. Immunohistochemical distribution of immunoreactive ERbeta in well-characterised menstrual cycle biopsy samples was lowest in proliferative endometrial glands, highest in early secretory phase glands and maintained at approximately 20% throughout the rest of the menstrual cycle and was closely correlated with stromal AR and stromal ERbeta expression. Stromal ERbeta was not significantly altered until the menstrual phase of the cycle and was not correlated with the expression of any other antigen in the stroma or endometrial glands except stromal AR. By contrast, glandular AR immunoreactivity was below 5% early in the cycle, increased during the secretory phase and showed strong expression just before menstruation. PR and Ki-67 expression showed strong positive correlations, indicating that PR may be a potent regulator of endometrial proliferation. These data suggest that glandular ERbeta expression is closely associated with a functional secretory role whereas glandular ERalpha and PR are associated with proliferation; glandular AR expression may be the switch required for menstruation.

Adult↗

PubMed2004

Mapping of a major locus that determines telomere length in humans.

Telomere length is a crucial factor for both normal chromosomal function and senescence. Mean telomere length in humans shows considerable interindividual variation and strong genetic determination. To see if a locus (or loci) affecting telomere length in humans could be mapped, we performed a quantitative-trait linkage analysis of mean leukocyte telomere-restriction-fragment (TRF) lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean (+/-SE) TRF was 81.9%+/-11.8%. There was significant linkage (LOD score 3.20) of mean TRF length to a locus on chromosome 12, which explained 49% of the overall variability in mean TRF length. We present preliminary analysis of a strong candidate gene in the region, the DNA helicase DDX11. In conclusion, we report mapping of the first locus that determines mean telomere length in humans. Identification of the gene involved and elucidation of its mechanism of action could have important implications for our understanding of chromosomal assembly, telomere biology, and susceptibility to age-related diseases.

Adolescent↗

PubMed2004

Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP.

OBJECTIVE: The platelet ADP receptors P2Y1 and P2Y12 play a pivotal role in platelet aggregation. There is marked interindividual variation in platelet response to ADP. We studied whether genetic variants in the P2Y1 or P2Y12 genes affect platelet response to ADP. METHODS AND RESULTS: The P2Y1 and P2Y12 genes were screened for polymorphisms. Associations between selected polymorphisms and the platelet response to ADP (0.1, 1.0, and 10 micromol/L), assessed by whole blood flow cytometric measurement of fibrinogen binding to activated glycoprotein IIb-IIIa, were then determined in 200 subjects. Five polymorphisms were found in the P2Y1 gene and 11 in the P2Y12 gene. All polymorphisms were silent. A P2Y1 gene dimorphism, 1622AG, was associated with a significant (P=0.007) effect on platelet ADP response, with a greater response in carriers of the G allele (frequency 0.15). The effect was seen at all concentrations of ADP but greatest at 0.1 mumol/L ADP, where the response in GG homozygotes was on average 130% higher than that seen in AA homozygotes (P=0.006). CONCLUSIONS: A common genetic variant at the P2Y1 locus is associated with platelet reactivity to ADP. This genotype effect partly explains the interindividual variation in platelet response to ADP and may have clinical implications with regard to thrombotic risk.

Adenosine Diphosphate↗

PubMed2004

An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization.

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person's genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met.

Confidence Intervals↗

PubMed2004

Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case-control study.

AIM: To identify polymorphisms and haplotypes in candidate genes that predispose to myocardial infarction (MI) using a multilocus approach. METHODS AND RESULTS: 1052 subjects, comprising 547 acute MI cases and 505 controls were studied. The association between MI and 58 SNPs in 35 candidate genes (generating 61 016 individual genotypes), and between MI and estimated haplotypes at 14 loci encompassing 16 genes was investigated. Two individual gene variants and haplotypes at two loci showed statistical association with MI. The alpha-adducin 460trp variant (OR 0.73, 95% CI 0.59-0.91, P=0.006) and the cholesteryl ester transfer protein -629A variant (OR 0.82, 95% CI 0.68-0.97, P=0.025) were both associated with a significant protective effect on MI, as was the paraoxonase 1/paraoxonase 2 haplotype comprising met55 and gln192 in paraoxonase 1 and cys311 in paraoxonase 2 (OR 0.52, 95% CI 0.39-0.77, P=0.001). The apolipoprotein C III haplotypes CCTTCG and ATCCCG at positions -641*-482*-455*1100*3175*3206 were associated with an increased risk of MI, odds ratios 1.41 (95% CI 1.06-1.76, P=0.023) and 1.71 (95% CI 1.28-2.14, P=0.038), respectively. CONCLUSIONS: We report associations of two polymorphisms and haplotypes at two loci with risk of MI that warrants testing in future studies. Furthermore, we demonstrate the application of a multilocus assay in the setting of a large association study and the additional benefit gained from the study of haplotypes to identify variants influencing risk of coronary heart disease.

Case-Control Studies↗

PubMed2004

Reaching low-income families: Focus group results provide direction for a behavioral approach to WIC services.

Supplemental Nutrition Program for Women, Infants, and Children (WIC) families were asked to identify motivators and barriers to health behavior change and preferred approaches to nutrition education in WIC. Six focus groups involved a total of 41 English-speaking WIC participants and addressed parenting, family meals, food preparation, and physical activity. The discussions were audiotaped, transcribed, and analyzed using NUD*IST software (Non-Numerical Unstructured Data Indexing, Searching, and Theorizing, version 4.0. Thousand Oaks, CA: Sage Publications Software, 1997). Key barriers to behavior change included inadequate parenting skills, lack of knowledge, unhealthy social environments, lack of time, and lack of social or financial support. Key motivators included feelings of responsibility, concern for child health and development, and positive social support. Participants identified facilitated discussions, support groups, cooking classes, and a WIC Web site as preferred methods of nutrition education. Results provided the foundation for the Healthy Habits nutrition education modules implemented in the Washington State WIC program and can be used to improve future nutrition education in WIC.

Adolescent↗

PubMed2004

Factors associated with success in first-time trabeculectomy for patients at low risk of failure with chronic open-angle glaucoma.

PURPOSE: To examine the relationships between study factors and trabeculectomy outcome in a representative sample of United Kingdom ophthalmology surgeons and patients. DESIGN: Cross-sectional observational study by questionnaire. PARTICIPANTS: All ophthalmic surgeons performing trabeculectomy in the National Health Service were invited to select their 4 most recent consecutive trabeculectomy cases satisfying study eligibility criteria before June 1996. Three hundred eighty-two surgeons supplied baseline data for 1450 patients and 1-year follow-up data for 1240 (85.3%) patients. All patients had undergone first-time trabeculectomy for chronic open-angle glaucoma. METHODS: Data were collected by self-administered questionnaires at baseline and 6 and 12 months postoperatively. Univariate analysis of the relationships between study factors and success was performed by chi-square test (categorical variables) and Student's t or Mann-Whitney U tests (continuous variables). Multiple logistic regression modeling of explanatory variables significant at a P value of </=0.1 was then performed. MAIN OUTCOME MEASURE: Trabeculectomy success, defined as a final intraocular pressure (IOP) less than two thirds of the preoperative IOP, excluding patients on antiglaucoma medications. RESULTS: After multiple logistic regression modeling, diabetes (odds ratio [OR] = 0.485, 95% confidence interval [CI] = 0.271-0.868, P = 0.015), superior rectus traction suture (OR = 0.580, 95% CI = 0.348-0.959, P = 0.034), subconjunctival anesthetic (OR = 0.172, 95% CI = 0.065-0.459, P<0.0001), and nonspecialist surgeons (OR = 0.539, 95% CI = 0.335-0.865, P = 0.010) remained significantly associated with poorer outcome. CONCLUSIONS: In this nationally representative sample of glaucoma patients undergoing first-time trabeculectomy, we have identified important associations between diabetes, superior rectus traction suture, subconjunctival anesthetic, nonspecialist surgeons, and diminished trabeculectomy success. These associations merit further examination.

Aged↗