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Age, cohort, and time-period confounds in aging research.

1. Cross-sectional studies of age-related changes or developmental patterns contain the inherent confound of age and cohort. 2. Longitudinal studies of age-related changes or developmental patterns contain the inherent confound of age and time-period. 3. Many complex research designs and decision rules have been developed in an attempt to disentangle these confounds. These designs and decision rules are only useful if their assumptions are met. 4. It is important to logically determine when the age, cohort, and time-period confounds discussed in this article are important to resolve in a nursing study and when the confounds do not directly relate to the clinical or theoretical merit of a study.

Aged↗

A longitudinal study on relations of retinol with parasitic infections and the immune response in children of Kikwawila village, Tanzania.

From 1982 to 1984 170 children of Kikwawila village (Kilombero district, Tanzania) were followed for nutritional (anthropometric measures, hematocrit, serum retinol, prealbumin, and zinc concentrations), parasitological (malaria parasitemia, urinary schistosomiasis, intestinal parasites) and immunological characteristics. Between 2.9% and 12.4% had serum retinol levels less than 100 micrograms/l which indicate deficiency. Retinol concentrations were correlated with age, hematocrits, prealbumin levels and mid upperarm circumferences. The latter correlation may be useful in nutritional surveys and primary health care programs for the identification of populations at risk of retinol deficiency. No association was found between average retinol levels and the presence of parasites, with the exception of malaria. Retinol levels were inversely correlated with malaria parasitemia in 1982, and directly correlated with antibody titers to synthetic sporozoite peptide in 1984. Since retinol, malaria parasitemia, and antisporozoite antibodies increased with age, confounding by age could not be excluded. Six months after administration of ornidazole in a single oral dose of 10 mg/kg, a significant effect on the prevalence of Giardia lamblia was found. Following treatment, average retinol levels were increased in persons with confirmed G. lamblia infections, but not in uninfected or untreated controls.

Adolescent↗

Increased serum cholesterol in healthy human methane producers is confounded by age.

It has been theorized that colonic production and absorption of short-chain fatty acids (SCFA) is different in methane producers (MP) compared with nonproducers (MNP). Because colonic SCFA may influence systemic lipid metabolism, blood lipids may differ in MP and MNP. To compare serum lipids and SCFA in fasting MP and MNP, we measured breath gases, serum lipids and SCFA in 167 healthy subjects and excluded subjects with abnormal blood lipids. The 66 MP were significantly older than the 63 MNP (49.5 +/- 16.0 vs. 39.6 +/- 17.0 y, P = 0.0009), and breath methane concentrations were weakly correlated with age in MP (r = 0.268, P = 0.03). Mean serum cholesterol was significantly higher in MP compared with MNP, but the differences were not significant after adjusting for age. No significant differences were observed in serum SCFA between the two groups. This study has shown that breath methane increases with age, which may be due to age-related increases in transit time and carbohydrate malabsorption. These results provide no conclusive link between colonic events and serum lipids in MP because, with age, methane production increased as did serum cholesterol. More research is required before any definite conclusions can be drawn.

Adult↗

Excessive testicular progesterone secretion in aged male Fischer 344 rats: a potential cause of age-related gonadotropin suppression and confounding variable in aging studies.

Previous studies have inconsistently reported elevated sex steroid levels in aging male F344 rats, which frequently develop testicular Leydig cell tumors. The aims of this study were to characterize circulating steroid levels and to determine the in vivo source and functional significance of altered steroid secretion in these animals. Progesterone (P) and to a lesser extent estradiol (E2) levels were increased, while gonadotropins and testosterone (T) were decreased, in intact 24-mo-old compared to 12-mo-old rats. P levels were inversely correlated with gonadotropins and T. All old rats demonstrated Leydig cell hyperplasia or tumors. After orchidectomy, P levels were markedly decreased. Gonadotropin levels were similar in orchidectomized 24-mo compared to 3-mo-old rats. We conclude that the testis is the source of excessive P and E2 secretion in vivo in old F344 rats. Increased P (or E2) negative feedback may contribute to the suppression of gonadotropins and reproductive function in aging male F344 rats. Finally, excessive P secretion may be a confounding pathological variable in aging studies using this rat model.

17-alpha-Hydroxyprogesterone↗

Age differences in movement time over distances proportional to size.

Investigations of the differences in movement speed over the age span, childhood to early adulthood, have typically confounded age with size differences which bring about mechanical differences in the task. The present study investigated the effect on arm movement time of confounding age and limb length. Young adults and children 7 to 9 yr. of age were tested over a distance proportional to their arm length. Despite moving over a proportionally shorter distance, the children were significantly slower than the adults, suggesting that age differences in performance are not solely attributable to size differences among subjects.

Adult↗

Minor physical anomalies in schizophrenia: is age a confounding factor?

Minor physical anomalies (MPAs) occur more frequently in a range of developmental disorders. They are also more frequent in schizophrenia supporting a neurodevelopmental aetiology of the illness. Contemporary MPA scales are yet to be validated for the effects of age. It is hypothesised that the effects of ageing may be confounding when these scales are applied to an elderly population. The distribution of MPAs in a normal elderly population was compared with younger subjects. Fifty subjects over the age of 60, and 50 subjects below the age of 60, with no known major mental illness, were evaluated. MPAs were assessed using a modified Lane scale [Psychol. Med. 27 (1997) 1155]. Elderly subjects showed an excess of absent trichions due to alopecia (p=0.004) short and broad palates (p=0.01) and greater ear protrusion (p=0.004) relative to young subjects. The differences reported are probably due to hair loss, edentulousness and growth of the auriculocephalic angle with age. These findings question the validity of studies of MPAs in schizophrenia that do not control for age.

Age Factors↗

Use of albumin as a predictor of mortality in community dwelling and institutionalized elderly populations.

This study was undertaken to identify variables that could explain the association between low albumin and a 9- to 12-year mortality follow-up among 287 community- dwelling and 176 institutionalized people aged 60 years and over. A wide array of nutrition assessment variables was simultaneously examined in this population to identify confounders of the association. The results show that the risk of mortality for subjects with albumin values of 40 g/liter and over was 0.46 of the risk for those with albumin values below 40 g/liter, after controlling for the confounders age, blood urea nitrogen, triglyceride, history of diseases, and inability to shop owing to medical conditions. Similarly, albumin was also inversely associated with mortality among institutionalized subjects even after controlling for the confounders age, sex, blood urea nitrogen, transferrin, and history of stroke. However, the association was no longer significant among the institutionalized population once the deaths that occurred within the first 3 years after study participation were eliminated. The results indicate that albumin is a long-term predictor of mortality among noninstitutionalized subjects and increased mortality is not only a result of age, history of chronic diseases, medication use, or protein intake. Among institutionalized subjects, albumin appeared to be a short-term predictor of mortality.

Aged↗

Why and how to control for age in occupational epidemiology.

In occupational epidemiology, the need to consider the age factor properly influences the choice of study design and analytical techniques. In most studies, age is viewed as a potential confounder. Age is strongly associated with end points of interest in occupational epidemiology (diseases, physiological characteristics, doses of xenobiotics, etc), but to measure age as a confounder it must be associated with the exposure under study. When the exposure of interest is time related-for example, duration of employment, time since first exposure, cumulative exposure-a strong intrinsic association with age can be anticipated, and age will behave as a (usually strong) confounder. When occupational exposures without a direct relation with age-for example, job, department, type of exposure-are evaluated, the degree and direction of confounding bias cannot be anticipated. Control of the confounding effect of age can be accomplished in the design phase of a study by way of randomisation, restriction, and matching. Randomisation is seldom viable in occupational settings. Restriction is rarely used in the case of age. Matching is often used in a case-control study as a method to increase the study efficiency, but it must be followed by proper matched or stratified analysis. Options for age adjustment in the analysis phase involve stratification and regression methods. In longitudinal studies the modified life table analysis is used to take into account the fact that subjects cross categories of age as the study proceeds. Stability of relative measures of effect over age strata favoured the greater use of relative risks than risk differences. In the presence of effect modification the influence of age should not be eliminated; its interaction with exposure should be explicitly considered.

Age Factors↗

Intra-abdominal adipose tissue deposition and parity.

OBJECTIVE: To determine the relationship between body composition/fat distribution and parity after adjusting for potential confounders: age, smoking, and physical activity. DESIGN: Cross-sectional. SUBJECTS: A total of 170 Caucasian women between the ages of 18 and 76 years, who were non-smokers with no cardiovascular disease, diabetes, metabolic, or endocrine disorders. MEASUREMENTS: Physical activity assessment (Baecke Physical Activity Questionnaire), anthropometric measures, and body composition (dual-energy X-ray absorptiometry, computed tomography). RESULTS: Although percent body fat was related to parity (r=0.26, P<0.01), after adjusting for age, physical activity index, and smoking, the parity-percent body fat relationship was no longer significant. Multiple regression analysis for modeling intra-abdominal adipose tissue demonstrated that parity and intra-abdominal adipose tissue were significantly related after adjusting for percent body fat, physical activity index, and smoking (partial r=0.18, P=0.02, unstandardized beta=5.22+/-2.26, intercept=-37.32+/-24.63). CONCLUSION: Our data suggest that intra-abdominal adipose tissue increases with increasing parity, even after adjusting for potential confounders: age, percent body fat, physical activity, and smoking.

Absorptiometry, Photon↗

Atrial ectopic activity and atrial fibrillation/flutter after coronary artery bypass surgery. A case-base study controlling for confounding from age, beta-blocker treatment, and time distance from operation.

To evaluate the impact of ectopic atrial activity and cardiac autonomic function for development of atrial fibrillation or flutter we studied 128 consecutive patients undergoing elective coronary artery bypass grafting. The patients were Holter monitored during a 96-h postoperative period. Autonomic balance was estimated by heart rate variability measurement. Thirty-eight (30%) patients developed sustained atrial fibrillation or flutter. Holter recordings were analyzed in a case-base design matching for age, beta-blocker treatment, and time elapsed after the operation. The number of supraventricular ectopic beats/h was increased (P < 0.01) in the case group during each of the last 7 h before onset of atrial fibrillation or flutter. Episodes of supraventricular tachycardia 62% vs. 26%; cases vs. controls (P = 0.007), episodes of non-sustained atrial fibrillation 29% vs. 0% (P = 0.0009), and episodes of non-sustained atrial flutter 15% vs. 0% (P = 0.05) were significant predictors of atrial fibrillation or flutter. Mean heart rate/h was increased in each of the 24 h preceding the arrhythmia. However, indexes of autonomic heart function did not differ significantly between groups. Patients developing atrial fibrillation or flutter after coronary artery bypass surgery present 'warning' atrial arrhythmias: numerous supraventricular ectopic beats, paroxysmal supraventricular tachycardia, and episodes of nonsustained atrial fibrillation and flutter.

Adrenergic beta-Antagonists↗

Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism.

INTRODUCTION: We propose that the increase in TNF-alpha and IL-6 in the brain in idiopathic parkinsonism is in response to a peripheral immune/ inflammatory process, so ubiquitous as to be responsible for the resemblance between ageing and parkinsonism. METHODS: Circulating cytokine was measured in 78 subjects with idiopathic parkinsonism and 140 without, aged 30 to 90 years, all obeying inclusion/exclusion criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by 1.37 (95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005). TNF-alpha appeared elevated in parkinsonians whose postural and psychomotor responses were abnormal, being suppressed where they were normal: trends which contrasted with those in controls (P = 0.015 and 0.05, respectively). Parkinsonism appeared (P = 0.08) to have an effect on IL-6, equivalent to that of >10 years of ageing (28(-3, 69)%), but was not immediately related to between-subject differences in performance. CONCLUSION: Ageing and pathogenetic insult may be confounded, age being a progression, not a risk, factor.

Adult↗

Age at menarche and age at menopause in relation to hepatocellular carcinoma in women.

OBJECTIVES: To assess whether age at menarche, age at menopause, parity, and selected blood hormones are associated with risk of hepatocellular carcinoma among women. DESIGN: Case-control. SAMPLE: and setting Data collected from 50 cases of hepatocellular carcinoma among women and 62 female controls with minor trauma or surgical conditions who attended one of three hospitals in Athens, Greece between 1995 and 1998. METHODS: Researchers collected information on Reproductive variables and assayed sera samples for blood hormone levels and for chronic infection with Hepatitis B and C viruses. RESULTS Individuals with hepatocellular carcinoma had a lower mean age at menarche and a significantly higher mean age at menopause. After adjusting for potential confounding, age at menopause remained an important and significant predictor, increasing the risk of hepatocellular carcinoma 24% for each later year of menopause (P < 0.001). For each year that menarche was delayed, risk of hepatocellular carcinoma declined 21% (P = 0.100). Mean levels of insulin-like growth factor-1 and its binding protein were significantly reduced in cases compared with controls, while levels of oestradiol, testosterone and sex hormone binding globulin were somewhat higher among the cases. CONCLUSIONS: This study provides indirect, but converging evidence that steroid hormones in general, and oestrogens in particular, play an important role in the aetiology of hepatocellular carcinoma among women.

Age Factors↗

Prepubertal height velocity references over a wide age range.

In order to correct height velocities for the confounders age and sex, SD scores can be calculated using the mean and the SD of the height velocity in the normal population. However, current methods are inappropriate for prepubertal children in the age range in which puberty occurs, because reference groups then consist of a mixed prepubertal/pubertal population. The mathematical infancy-childhood-puberty (ICP) model opens up the possibility of dissecting the puberty component from the total growth curve. New references for height velocity for prepubertal children calculated over a 12 month interval up to the ages of 15.5 years (boys) and 13.5 years (girls) have been constructed on the basis of adaptations of the ICP model and the Swedish longitudinal growth study.

Age Factors↗

Chorionic villus sampling and transverse limb deficiencies: maternal age is not a confounder.

Advanced maternal age is a frequent indication for performing chorionic villus sampling (CVS) and it might be a confounder of the association between transverse limb deficiencies (TLD) and early CVS. We have first analyzed the maternal age-specific rates of TLD in the population monitored by the Italian Multicentric Birth Registry; then we updated a case control study controlling for maternal age. The rate of all limb deficiencies (LD) was 5.9 per 10,000 births. No trend for an excess risk for TLD or other LD with advancing maternal age was found. The relative risk for women 35 years of age and older vs. those under 35 was 0.92 (95% CI, 0.72-1.19) for any LD and 0.99 (95% CI, 0.71-1.39) for TLD. In the case control study, 11 mothers of case patients with a TLD had been exposed to CVS out of a total of 206 (5.3%), compared to 54 mothers of control patients with defects other than TLD out of a total of 12,140 (0.4%). The risk estimate for TLD associated with CVS was high in the overall analysis (OR, 12.63) and did not decrease after stratification, both in the overall sample (Mantel-Haenszel OR, 14.01) and in each gestational age stratum. Thus, advanced maternal age does not explain the association between CVS and TLD found in this study and it is unlikely to explain that observed in the several other positive studies. We recommend that any study addressing the relationship between CVS and LD should include a careful evaluation of the type of LD and the timing of CVS, and present the results for specific gestational age periods.

Adult↗

Passive smoking as well as active smoking increases the risk of acute stroke.

OBJECTIVE: To estimate the relative risk of stroke associated with exposure to environmental tobacco smoke (ETS, passive smoking) and to estimate the risk of stroke associated with current smoking (active smoking) using the traditional baseline group (never-smokers) and a baseline group that includes lifelong non-smokers and long-term (> 10 years) ex-smokers who have not been exposed to ETS. DESIGN AND SETTING: Population-based case-control study in residents of Auckland, New Zealand. SUBJECTS: Cases were obtained from the Auckland stroke study, a population-based register of acute stroke. Controls were obtained from a cross-sectional survery of major cardiovascular risk factors measured in the same population. A standard questionnaire was administered to patients and controls by trained nurse interviewers. RESULTS: Information was available for 521 patients with first-ever acute stroke and 1851 community controls aged 35-74 years. After adjusting for potential confounders (age, sex, history of hypertension, heart disease, and diabetes) using logistic regression, exposure to ETS among non-smokers and long-term ex-smokers was associated with a significantly increased risk of stroke (odds ratio (OR) = 1.82; 95% confidence interval (95% CI) = 1.34 to 2.49). The risk was significant in men (OR = 2.10; 95% CI = 1.33 to 3.32) and women (OR = 1.66; 95% CI = 1.07 to 2.57). Active smokers had a fourfold risk of stroke compared with people who reported they had never smoked cigarettes (OR = 4.14; 95% CI = 3.04 to 5.63); the risk increased when active smokers were compared with people who had never smoked or had quit smoking more than 10 years earlier and who were not exposed to ETS (OR = 6.33; 95% CI = 4.50 to 8.91). CONCLUSIONS: This study is one of the few to investigate the association between passive smoking and the risk of acute stroke. We found a significantly increased risk of stroke in men and in women. This study also confirms the higher risk of stroke in men and women who smoke cigarettes compared with non-smokers. The stroke risk increases further when those who have been exposed to ETS are excluded from the non-smoking reference group. These findings also suggest that studies investigating the adverse effects of smoking will underestimate the risk if exposure to ETS is not taken into account.

Acute Disease↗