The Lausanne-Geneva cohort study of offspring of parents with mood disorders: methodology, findings, current sample characteristics, and perspectives.

PURPOSE: Studies focusing on the offspring of affected parents utilize the well-established familial aggregation of mood disorders as a powerful tool for the identification of risk factors, early clinical manifestations, and prodromes of mood disorders in these offspring. The major goals of the Lausanne-Geneva mood cohort study are to: (1) assess the familial aggregation of bipolar and unipolar mood disorders; (2) prospectively identify risk factors for mood disorders as well as their early signs and prodromes; (3) identify their endophenotypes including cognitive features, alterations in brain structure, HPA-axis dysregulation, and abnormalities of the circadian rhythm of activity. METHODS: Probands with bipolar disorders, major depressive disorder, and controls with at least one child aged from 4 to 17.9 years at study intake, their offspring, as well as their spouses are invited to take part in follow-up assessments at predetermined ages of the offspring. Direct semi-structured diagnostic interviews have been used for all participants. Probands, spouses, and adult offspring also undergo neurocognitive testing, anthropomorphic measures and biochemical exams, structural Magnetic Resonance Imaging, as well as objective assessments of physical activity using accelerometers in combination with ecological momentary assessments. RESULTS: Currently, our study has up to seven follow-up assessments extending over a period of 20 years. There are 214 probands and 389 offspring with one direct interview before age 18 as well as a second assessment over follow-up. Data on 236 co-parents are also available from whom 55% have been directly interviewed. First publications support the specificity of the familial aggregation of BPD and the strong influence of an early onset of the parental BPD, which amplifies the risk of developing this disorder in offspring. CONCLUSIONS: Information from clinical, biological, cognitive, and behavioral measures, based on contemporary knowledge, should further enhance our understanding of mood disorder psychopathology, its consequences, and underlying mechanisms.

Mental disorders in offspring of parents with bipolar and major depressive disorders.

OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS: These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.

Risk of mental disorders in children of parents with alcohol or heroin dependence: a controlled high-risk study.

AIM: To assess the specific effect of alcohol dependence (AD) or heroin dependence (HD) in patients and their spouses on the risk of psychopathology in their 276 6.0- to 17.9- year-old children (mean 11.3 years). METHODS: The sample included 101 offspring of patients with AD, 23 of patients with HD, and 152 of medical controls, as well as their 2 parents. Participants were assessed using semistructured diagnostic interviews and family history reports by psychologists blind to patient diagnoses. RESULTS: Children of HD and AD patients had largely elevated rates of recurrent major depressive disorder. Children of HD patients were also at an increased risk for attention deficit hyperactivity disorder and substance use disorders (SUD). There were interactions between SUD in the 2 parents to increase the risk of SUD in offspring. CONCLUSIONS: These results emphasize the need for prompt identification and treatment of these children and highlight the need to pay clinical attention not only to the patient, but also to the co-parent in order to optimize prevention in offspring.

European collaborative study of early-onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset.

Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.

Parent-child agreement and prevalence estimates of diagnoses in childhood: direct interview versus family history method.

Diagnostic information on children is typically elicited from both children and their parents. The aims of the present paper were to: (1) compare prevalence estimates according to maternal reports, paternal reports and direct interviews of children [major depressive disorder (MDD), anxiety and attention-deficit and disruptive behavioural disorders]; (2) assess mother-child, father-child and inter-parental agreement for these disorders; (3) determine the association between several child, parent and familial characteristics and the degree of diagnostic agreement or the likelihood of parental reporting; (4) determine the predictive validity of diagnostic information provided by parents and children. Analyses were based on 235 mother-offspring, 189 father-offspring and 128 mother-father pairs. Diagnostic assessment included the Kiddie-schedule for Affective Disorders and Schizophrenia (K-SADS) (offspring) and the Diagnostic Interview for Genetic Studies (DIGS) (parents and offspring at follow-up) interviews. Parental reports were collected using the Family History - Research Diagnostic Criteria (FH-RDC). Analyses revealed: (1) prevalence estimates for internalizing disorders were generally lower according to parental information than according to the K-SADS; (2) mother-child and father-child agreement was poor and within similar ranges; (3) parents with a history of MDD or attention deficit hyperactivity disorder (ADHD) reported these disorders in their children more frequently; (4) in a sub-sample followed-up into adulthood, diagnoses of MDD, separation anxiety and conduct disorder at baseline concurred with the corresponding lifetime diagnosis at age 19 according to the child rather than according to the parents. In conclusion, our findings support large discrepancies of diagnostic information provided by parents and children with generally lower reporting of internalizing disorders by parents, and differential reporting of depression and ADHD by parental disease status. Follow-up data also supports the validity of information provided by adolescent offspring.

Personality traits in children of parents with unipolar and bipolar mood disorders.

BACKGROUND: Using family study data, the following questions regarding the mechanisms of association between personality traits and mood disorders were addressed: 1) Is there an association between unipolar and bipolar mood disorders and personality traits in probands? 2) Are personality traits associated with depression in their 9 to 17 year-old children? 3) Is there an association between parental mood disorders and personality traits in offspring? 4) Are parental personality traits associated with the risk of depression in offspring? METHODS: The study included 50 probands with bipolar and 37 with unipolar mood disorder, 34 healthy controls as well as 178 of their children between 9 and 17 years. Diagnoses were made according to a best-estimate procedure based on a semi-structured interview (DIGS), medical records and family history information. Personality traits were assessed using the Eysenck Personality Questionnaire in adults and the Eysenck Personality Questionnaire Junior in offspring. RESULTS: Personality traits, and in particular Neuroticism, were found to be associated with mood disorders in currently affected as well as remitted probands and offspring. However, there was no association between mood disorders in parents and personality traits in their children, and conversely, parental personality traits were not associated with the risk of depression in offspring. LIMITATIONS: 1) Relatively small proportion of offspring who were still unaffected but likely to subsequently develop mood disorders; 2) cross-sectional design. CONCLUSIONS: The findings were best compatible with the complication or scar hypothesis, which assumes the occurrence of abnormal personality traits as a consequence of previous depressive episodes.

Sex differences in symptom patterns of recurrent major depression in siblings.

The objectives of this study were to examine sex differences in depressive symptom patterns in 475 sib pairs with well-defined recurrent major depression and to test the hypotheses that (a) symptom patterns show higher intraclass correlations within same sex sib pairs versus mixed sex sib pairs; and (b) symptoms more associated with women, e.g. atypical depressive and anxiety symptoms, account for differences between male and female siblings within the same family. A total of 878 individuals, with a past history of at least two depressive episodes, were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry interview and diagnosed according to DSM-IV using a computerized scoring program (CATEGO5). Intraclass correlations were compared between mixed and same sex sibs, and a conditional regression analysis in mixed sex sib pairs was performed to test whether specific symptoms account for differences between male and female siblings within the same family. Women showed a significantly earlier onset of depression compared with men (23.0 years, SD=10.6 versus 25.5, SD=12.5 years, P=0.0004), and a significantly greater frequency of several aspects of depressed mood was found in women compared with men, including atypical depressive features of fatiguability, appetite gain, weight gain and hypersomnia. Discordant sib-pair data analyses revealed five symptoms that accounted for the sex differences between siblings (P=.000035): phobia (exp(B)=2.04, P=0.017), hypersomnia (exp(B)=1.37, P=0.055), appetite loss (exp(B)=1.38, P=0.004) and appetite gain (exp(B)=2.19, P<0.001). Sex significantly modifies clinical features of depression and an earlier onset of depression and atypical depressive symptoms occur more frequently in women.

Inter-informant agreement on diagnoses and prevalence estimates of anxiety disorders: direct interview versus family history method.

The aims of the present study were to: (1) assess agreement for diagnoses of specific anxiety disorders between direct interviews and the family history method; (2) compare prevalence estimates according to direct interviews and family history information; (3) test strategies to approximate prevalence estimates according to family history reports to those based on direct interviews; (4) test covariates of inter-informant agreement; and (5) test the likelihood of reporting disorders by informants. Analyses were based on family study data which included 1625 distinct informant (first-degree relatives and spouses)-index subject pairs. Our main findings were: (1) inter-informant agreement was satisfactory for panic disorder, agoraphobia, social phobia and obsessive-compulsive disorder; (2) the family history method provided lower prevalence estimates for all anxiety disorders (except for generalized anxiety disorder and obsessive-compulsive disorder) than direct interviews; (3) the lowering of diagnostic thresholds and the combination of multiple family history reports increased the accuracy of prevalence estimates according to the family history method; (4) female gender of index subjects was associated with poor agreement; and (5) informants, who themselves had a history of an anxiety disorder, were more likely to detect this disorder in their relatives which entails the risk of overestimation of the size of familial aggregation.

[Income and expenses of patients with chronic psychosis]. / Revenus et dépenses des patients souffrant de psychose chronique.

Knowledge about the income of patients with chronic psychotic disorder and how they use the money may help to provide appropriate clinical and social assistance. Fifty-seven outpatients with schizophrenia treated in Geneva, Switzerland, were studied. Mean income was 3866 Swiss francs (4209 for those with the Swiss disability fund). Only a minority of patients live on meager resources with insufficient comfort. A 4 weeks follow-up showed that patients disposed of a mean of 400 Swiss francs discretionary money. Twenty eight percent of this money was used for leisure activities. This psychiatric and social system allows stabilized patients with psychosis to get what they need in terms of financial support and housing. However, patients should be helped to use their discretionary money in ways more prone to help recovery.

Using venlafaxine to treat behavioral disorders in patients with autism spectrum disorder.

OBJECTIVE: To test the efficacy of venlafaxine at a dose of 18.75 mg/day on the reduction of behavioral problems such as irritability and hyperactivity/noncompliance in patients with intellectual disabilities and autism spectrum disorder (ASD). Our secondary hypothesis was that the usual doses of zuclopenthixol and/or clonazepam would decrease in the venlafaxine-treated group. METHODS: In a randomized double-blind study, we compared six patients who received venlafaxine along with their usual treatment (zuclopenthixol and/or clonazepam) with seven patients who received placebo plus usual care. Irritability, hyperactivity/noncompliance, and overall clinical improvement were measured after 2 and 8 weeks, using validated clinical scales. RESULTS: Univariate analyses showed that the symptom of irritability improved in the entire sample (p = 0.023 after 2 weeks, p = 0.061 at study endpoint), although no difference was observed between the venlafaxine and placebo groups. No significant decrease in hyperactivity/noncompliance was observed during the study. At the end of the study, global improvement was observed in 33% of participants treated with venlafaxine and in 71% of participants in the placebo group (p = 0.29). The study found that decreased cumulative doses of clonazepam and zuclopenthixol were required for the venlafaxine group. Multivariate analyses (principal component analyses) with at least three combinations of variables showed that the two populations could be clearly separated (p b 0.05). Moreover, in all cases, the venlafaxine population had lower values for the Aberrant Behavior Checklist (ABC), Behavior Problems Inventory (BPI), and levels of urea with respect to the placebo group. In one case, a reduction in the dosage of clonazepam was also suggested. For an additional set of variables (ABC factor 2, BPI frequency of aggressive behaviors, hematic ammonia at Day 28, and zuclopenthixol and clonazepam intake), the separation between the two samples was statistically significant as was the Bartlett's test, but the Kaiser­Meyer­Olkin Measure of Sampling Adequacy was below the accepted threshold. This set of variables showed a reduction in the cumulative intake of both zuclopenthixol and clonazepam. CONCLUSION: Despite the small sample sizes, this study documented a statistically significant effect of venlafaxine. Moreover, we showed that lower doses of zuclopenthixol and clonazepam were needed in the venlafaxine group, although this difference was not statistically significant. This was confirmed by multivariate analyses, where this difference reached statistical significance when using a combination of variables involving zuclopenthixol. Larger-scale studies are recommended to better investigate the effectiveness of venlafaxine treatment in patients with intellectual disabilities and ASD.

Monoamine oxidase a and tryptophan hydroxylase gene polymorphisms: are they associated with bipolar disorder?

Most of the candidate gene studies in bipolar disorder have focused on the major neurotransmitter systems that are influenced by drugs used in the treatment of this disorder. The monoamine oxidase A (MAOA) and the tryptophan hydroxylase (TPH1, TPH2) genes are two of the candidates that have been tested in a series of association studies using unrelated or family-based controls. This review summarizes the existing association studies regarding these genes. Most of these studies were based on the unrelated case-control design with samples of 50 to 600 subjects. Regarding MAOA, three meta-analyses with partially overlapping samples supported a modest effect of this gene in bipolar disorder in female Caucasians. However, as several studies could not replicate these findings, more work is necessary to demonstrate unequivocally the involvement of MAOA in bipolar disorder and establish the biological mechanism underlying the genetic association. With respect to TPH1 and TPH2, the majority of studies did not provide evidence for an association between these genes and bipolar disorder. The genes are more likely to be related to suicidal behavior than to bipolar disorder.

Familiality of symptom dimensions in depression.

BACKGROUND: Depression is a clinically heterogeneous disorder thought to result from multiple genes interacting with environmental and developmental components. A dimensional rather than a categorical approach to depressive phenotype definition may be more useful for identification of susceptibility genes. OBJECTIVES: To perform an exploratory factor analysis on a range of depressive and anxiety symptoms in a large, well-defined sample of depressed siblings, as well as a confirmatory factor analysis in a separate large group of unrelated depressed subjects, and to analyze correlations of identified symptom dimensions between depressed siblings. DESIGN: Subjects (N = 1034), including 475 sibling pairs, with a history of at least 2 depressive episodes were recruited from the Depression Network Study, a large-scale multicenter collection of families affected by recurrent unipolar depression. Subjects were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to the DSM-IV and the International Classification of Diseases, 10th Revision, using a computerized scoring program (CATEGO5). Factor analysis was carried out on 26 depression symptom items, including 4 anxiety screening items. Confirmatory factor analysis was performed on an independent sample of 485 depressed individuals. RESULTS: Four interpretable factors were identified: (1) mood symptoms and psychomotor retardation; (2) anxiety; (3) psychomotor agitation, guilt, and suicidality; and (4) appetite gain and hypersomnia. For each symptom group, a quantitative scale was constructed, and correlations between siblings were calculated. There was a moderate degree of sibling homotypia for some depressive symptoms, and factors 1, 2, and 3 showed significant positive familial correlation (0.145 [P =.001], 0.335 [P<.001], and 0.362 [P<.001], respectively). CONCLUSIONS: This is the first study of large, well-defined samples of depressed subjects in whom symptom dimensions have been derived and then confirmed using independent material. The significant correlations between siblings for 3 of the dimensions suggest substantial familial, perhaps genetic, etiologies.

Intensive dialectical behavior therapy for outpatients with borderline personality disorder who are in crisis.

OBJECTIVE: This study examined the effectiveness of an intensive version of dialectical behavior therapy for patients in an outpatient setting who met criteria for borderline personality disorder and who were in crisis. METHODS: Over the two-year study period, 127 patients (103 women) between the ages of 18 and 52 years were referred to the program; 87 were admitted, and because of a limited number of places, 40 were referred elsewhere. Patients were admitted after recent suicidal or parasuicidal behavior, and the most suicidal patients were given priority. The treatment was a three-week intensive version of dialectical behavior therapy consisting of individual therapy sessions; an emphasis on skills training provided in groups, including mindfulness skills; and team consultation. A diagnostic interview was administered, and patients were screened with the International Personality Disorder Examination Screening Questionnaire, the Beck Depression Inventory (BDI), the Beck Hopelessness Scale (BHS), and the Social Adaptation Self-Evaluation Scale. RESULTS: The only significant difference at intake between patients admitted to the program and those referred elsewhere was a slighter higher incidence of antisocial traits in the latter group. Of the 87 patients admitted, 71 (82 percent) completed the program and 16 (18 percent) dropped out. Pre-post analysis showed significant improvement in scores on the BDI and BHS. CONCLUSIONS: The three-week, intensive version of dialectical behavior therapy was found to be an effective treatment. Treatment completion was high, and patients showed statistically significant improvements in depression and hopelessness measures. This approach allowed therapists to treat a large number of patients in a short time.

Assessing efficacy of chronic therapy when disease is characterized by frequent relapses: the example of schizophrenia.

In assessing the efficacy of therapy for schizophrenia, the effect of medication on relapse needs to be distinguished from the influence of relapse on medication. Typically, effective medication prevents relapse, but relapse generally induces medication. Conventional analyses using either treatment or disease as outcome do not separate these two effects. We propose an alternate approach that uses both treatment and schizophrenic relapse as random variables. Data from 58 schizophrenic patients, with up to 60 consecutive monthly determinations of antipsychotic medication and schizophrenic events, were analyzed using a bivariate transition model with random effects. This analysis revealed that the risk of current schizophrenic relapse is reduced by continuous medication (previous month and current month) but not necessarily by discontinuous medication.

Diagnostic interview for genetic studies (DIGS): inter-rater and test-retest reliability of alcohol and drug diagnoses.

The semi-structured diagnostic interview for genetic studies (DIGS) was developed to assess major mood and psychotic disorders and their spectrum manifestations in genetic studies. Our research group developed a French version of the DIGS and tested its inter-rater and test-retest reliability in psychiatric patients. In this article, we present estimates of the reliability of substance use and antisocial personality disorders. High kappa coefficients for inter-rater reliability were found for drug and alcohol as well as antisocial personality diagnoses and slightly lower kappas for test-retest reliability. Combined with evidence of the reliability of major mood and psychotic disorders, these findings support the suitability of the DIGS for studies of familial aggregation and comorbidity of psychiatric disorders including substance use and antisocial personality disorders.

Patients' satisfaction with hospitalization in a mixed psychiatric and somatic care unit.

A patient satisfaction survey was undertaken in a mixed psychiatric and somatic care unit. An anonymous self-report questionnaire covering setting and satisfaction with care was completed by 60 patients. Median age was 42 (range 20-64), and the majority female (63%). Main ICD-10 diagnostic categories were depressive disorders (51.7%), substance-related disorders (33%) and personality disorders (25%). Somatic comorbidity was present in 60% of patients. Overall satisfaction with care and setting was high. Higher satisfaction was significantly associated with a history of previous hospitalizations in a psychiatric hospital and with being referred to the program by a psychiatrist. These findings emphasize the perceived advantages of mixed units, such as decreased stigmatization of psychiatric inpatients and opportunity to receive adequate treatment for both physical and mental problems during a single hospital stay.

Associations between alcohol consumption and selected cytokines in a Swiss population-based sample (CoLaus study).

OBJECTIVE: To assess the associations between alcohol consumption and cytokine levels (interleukin-1beta - IL-1ß; interleukin-6 - IL-6 and tumor necrosis factor-α - TNF-α) in a Caucasian population. METHODS: Population sample of 2884 men and 3201 women aged 35-75. Alcohol consumption was categorized as nondrinkers, low (1-6 drinks/week), moderate (7-13/week) and high (14+/week). RESULTS: No difference in IL-1ß levels was found between alcohol consumption categories. Low and moderate alcohol consumption led to lower IL-6 levels: median (interquartile range) 1.47 (0.70-3.51), 1.41 (0.70-3.32), 1.42 (0.66-3.19) and 1.70 (0.83-4.39) pg/ml for nondrinkers, low, moderate and high drinkers, respectively, p<0.01, but this association was no longer significant after multivariate adjustment. Compared to nondrinkers, moderate drinkers had the lowest odds (Odds ratio=0.86 (0.71-1.03)) of being in the highest quartile of IL-6, with a significant (p<0.05) quadratic trend. Low and moderate alcohol consumption led to lower TNF-α levels: 2.92 (1.79-4.63), 2.83 (1.84-4.48), 2.82 (1.76-4.34) and 3.15 (1.91-4.73) pg/ml for nondrinkers, low, moderate and high drinkers, respectively, p<0.02, and this difference remained borderline significant (p=0.06) after multivariate adjustment. Moderate drinkers had a lower odds (0.81 [0.68-0.98]) of being in the highest quartile of TNF-α. No specific alcoholic beverage (wine, beer or spirits) effect was found. CONCLUSIONS: Moderate alcohol consumption is associated with lower levels of IL-6 and (to a lesser degree) of TNF-α, irrespective of the type of alcohol consumed. No association was found between IL-1ß levels and alcohol consumption.

Association between inflammatory and obesity markers in a Swiss population-based sample (CoLaus Study).

OBJECTIVE: To assess the associations between obesity markers (BMI, waist circumference and %body fat) and inflammatory markers (interleukin-1ß (IL-1ß); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein (hs-CRP)). METHODS: Population sample of 2,884 men and 3,201 women aged 35-75 years. Associations were assessed using ridge regression adjusting for age, leisure-time physical activity, and smoking. RESULTS: No differences were found in IL-1ß levels between participants with increased obesity markers and healthy counterparts; multivariate regression showed %body fat to be negatively associated with IL-1ß. Participants with high %body fat or abdominal obesity had higher IL-6 levels, but no independent association between IL-6 levels and obesity markers was found on multivariate regression. Participants with abdominal obesity had higher TNF-α levels, and positive associations were found between TNF-α levels and waist circumference in men and between TNF-α levels and BMI in women. Obese participants had higher hs-CRP levels, and these differences persisted after multivariate adjustment; similarly, positive associations were found between hs-CRP levels and all obesity markers studied. CONCLUSION: Obesity markers are differentially associated with cytokine levels. %Body fat is negatively associated with IL-1ß; BMI (in women) and waist circumference (in men) are associated with TNF-α; all obesity markers are positively associated with hs-CRP.

Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study).

OBJECTIVE: to assess the levels and determinants of interleukin (IL)-1ß, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) in a healthy Caucasian population. METHODS: population sample of 2884 men and 3201 women aged 35 to 75. IL-1ß, IL-6 and TNF-α were assessed by a multiplexed particle-based flow cytometric assay and CRP by an immunometric assay. RESULTS: Spearman rank correlations between duplicate cytokine measurements (N = 80) ranged between 0.89 and 0.96; intra-class correlation coefficients ranged between 0.94 and 0.97, indicating good reproducibility. Among the 6085 participants, 2289 (37.6%), 451 (7.4%) and 43 (0.7%) had IL-1ß, IL-6 and TNF-α levels below detection limits, respectively. Median (interquartile range) for participants with detectable values were 1.17 (0.48-3.90) pg/ml for IL-1ß; 1.47 (0.71-3.53) pg/ml for IL-6; 2.89 (1.82-4.53) pg/ml for TNF-α and 1.3 (0.6-2.7) ng/ml for CRP. On multivariate analysis, greater age was the only factor inversely associated with IL-1ß levels. Male sex, increased BMI and smoking were associated with greater IL-6 levels, while no relationship was found for age and leisure-time PA. Male sex, greater age, increased BMI and current smoking were associated with greater TNF-α levels, while no relationship was found with leisure-time PA. CRP levels were positively related to age, BMI and smoking, and inversely to male sex and physical activity. CONCLUSION: Population-based levels of several cytokines were established. Increased age and BMI, and to a lesser degree sex and smoking, significantly and differentially impact cytokine levels, while leisure-time physical activity has little effect.