Dr Isabelle Carrière
email: isabelle.carriere@inserm.fr

A Farré

C Proust-Lima

J Ryan

M L Ancelin

K Ritchie

Chronic and remitting trajectories of depressive symptoms in the elderly. Characterization and risk factors

Keywords: depressive symptoms, aged, risk factors, cohort studies

Aims

In elderly general population sub-syndromal clinically significant levels of depressive symptoms are highly prevalent and associated with high co-morbidity and increased mortality risk. However changes in depressive symptoms over time and etiologic factors have been difficult to characterize notably due to methodological shortcomings. Our objective was to differentiate trajectories of depressive symptoms over 10 years in community-dwelling elderly men and women using statistical modelling methods which take into account intra-subject correlation and individual differences as well as to examine current and life-time risk factors associated with different trajectories. symptom course in both gender as well as diabetes in men (OR=3.5, 95% CI 1.1-10.9) and childhood traumatic experiences in women (OR=3.1, 95% CI 1.6-5.8).

Conclusions

This prospective study was able to differentiate patterns of chronic and remitting depressive symptoms in elderly people with distinct symptom courses and risk factors for men and women. These findings may inform prevention programmes designed to reduce the chronic course of depressive symptomatology.

Methods

Participants aged 65 and over were administered standardised questionnaires and underwent clinical examinations at baseline and after 2, 4, 7 and 10 years. Trajectories over time of the Center for Epidemiologic Studies Depression scores were modelled in 517 men and 736 women separately with latent class mixed models which include both a linear mixed model to describe latent classes of trajectories and a multinomial logistic model to characterize the latent trajectories according to baseline covariates (socio-demographic, lifestyle, clinical, genetic characteristics and stressful life events).

Results

In both genders two different profiles of symptom changes were observed over the 10-year follow-up.

For 9.1% of men and 25% of women a high depressive symptom trajectory was found with a trend toward worsening in men. The majority of the remaining men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels of depressive symptoms. In large multivariate class membership models, mobility limitations (odds ratio (OR)=4.5, 95% confidence interval (CI) 1.6-12.9 and OR=4.9, 95% CI 2.3-10.7, in men and women respectively), ischemic pathologies (OR=2.9, 95% CI 1.0-8.3 and OR=3.1, 95%CI 1.0-9.9), and recent stressful events (OR=4.5, 95% CI 1.1-18.5, OR=3.2, 95%CI 1.6-6.2) were associated with a poor

INTRODUCTION

Most community-dwelling elderly people who have clinically significant levels of depressive symptomatology do not meet the full diagnostic criteria for major depressive episodes [START_REF] Blazer | Depression in late life: review and commentary[END_REF][START_REF] Cuijpers | Differential mortality rates in major and subthreshold depression: meta-analysis of studies that measured both[END_REF]. Studies of depression in the elderly have thus increasingly focused on levels of depressive symptomatology rather than diagnostic categories, as this takes into account clinically significant sub-syndromal states; the latter being not only highly prevalent in the elderly (12-15%), but also associated with high co-morbidity, high mortality, and treatment resistance [START_REF] Helmchen | Subthreshold disorders in psychiatry: clinical reality, methodological artifact, and the double-threshold problem[END_REF][START_REF] Kirsch | Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration[END_REF][START_REF] Olfson | Subthreshold psychiatric symptoms in a primary care group practice[END_REF].

Previous studies have suggested that depressive states in the elderly may have a highly variable course due to their diverse origins. Very few studies in the general elderly population have undertaken the complex task of characterizing dimensional symptom trajectories over a long time period. One study considered a priori trajectory groups instead of estimating them [START_REF] Chen | Trajectories of depression and their relationship with health status and social service use[END_REF], while others used methods such as non-parametric K-means clustering [START_REF] Cui | Outcomes and predictors of late-life depression trajectories in older primary care patients[END_REF] or a semi-parametric latent class growth analysis [START_REF] Andreescu | Twelve-year depressive symptom trajectories and their predictors in a community sample of older adults[END_REF][START_REF] Byers | Twenty-year depressive trajectories among older women[END_REF][START_REF] Hsu | Group-based trajectories of depressive symptoms and the predictors in the older population[END_REF][START_REF] Jones | Advances in group-based trajectory modelling and an SAS procedure for estimating them[END_REF][START_REF] Liang | Multiple trajectories of depressive symptoms in middle and late life: racial/ethnic variations[END_REF] which do not fully take into account intra-subject correlation (correlation between repeated evaluations of the same subject). One recent study [START_REF] Kuchibhatla | Trajectory classes of depressive symptoms in a community sample of older adults[END_REF] used a more complex method, the generalized growth mixture model [START_REF] Muthen | General growth mixture modeling for randomized preventive interventions[END_REF], which takes into account both intra-subject correlation and individual variability in depressive symptom curves over time within each trajectory group. This study included covariates such as self-rated health, cognition, functional disability, social network, and recent stressful events, but not other major risk factors for depression in the elderly such as chronic diseases and early-life stressors [START_REF] Cole | Risk factors for depression among elderly community subjects: a systematic review and meta-analysis[END_REF]Ritchie et al., 2009;Vink et al., 2008). Possible gender differences in clinical trajectories were also not examined, although such differences have consistently been observed in the levels, characteristics, and course of depressive symptoms [START_REF] Carriere | Late life depression and incident activity limitations: influence of gender and symptom severity[END_REF]Piccinelli & Wilkinson, 2000;Ryan et al., 2008). In women symptom levels tend to be higher and chronicity of depression appears to have a greater impact, perhaps due to over reporting of symptoms, psychological, neurochemical, hormonal, genetic, and personality factors, and higher stress reactivity [START_REF] Grigoriadis | Gender issues in depression[END_REF]. Given these differences it would be clinically more useful to examine the course of depressive symptoms separately in men and women. This would furthermore enable the establishment of thresholds for the early detection of persons at high risk of a severe and unremitting disease course.

The present study has two aims: i) to examine trajectories of depressive symptoms over a 10-year period for men and women separately, using statistical modelling methods which take into account intra-subject correlation and individual differences, and ii) to examine a wide range of current and lifetime risk and protective factors potentially associated with different trajectories. Identifying factors contributing to depressive symptom chronicity and remission in men and women may subsequently be useful to indicate potential intervention windows.

MATERIAL AND METHODS

Study sample

Participants of the ESPRIT study were recruited over a 2-year period from 1999 to 2001 (Ritchie et al., 2004), by random selection from the electoral rolls in Montpellier, France. Eligible people, who were at least 65 years of age and non-institutionalised, were invited to participate and provided written informed consent. Of the people initially drawn at random, 27.3% did not participate. Those who refused to participate were replaced by another person drawn at random from the same electoral division to ensure representativeness. Participants were administered a number of standardised questionnaires by trained staff and underwent clinical examinations at baseline, 2, 4, 7, and 10 years of follow-up. Ethics approval was granted by the Ethics Committee of the University Hospital of Kremlin-Bicêtre (France). Informed consent was obtained from all individual participants included in the study.

Of the 2259 participants included in the cohort, 1988 subjects (816 men and 1172 women) with at least two repeated measures of depressive symptoms throughout the 10-year period were at first selected. Of these, 735 subjects with missing data for at least one baseline covariate were excluded (of them 481 had incomplete responses to the childhood event questionnaire) leaving 1253 (517 men and 736 women) in the main analysis. Sensitivity analysis for detection of trajectories was also performed on the full sample of 1988 participants.

Compared with the participants included in the analysis, those excluded were older, with a lower level of education, and were more likely to be treated with antidepressants and to have mobility limitations, ischemic pathologies, low cognitive performance, and depressive symptomatology. They were also more likely to have lack of support during childhood (p<0.001 for all comparisons). There were no significant differences regarding gender, past major depressive episode and 5-HTTLPR genotype.

Depressive symptoms

Depressive symptoms were evaluated at each wave using the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff, 1977), a 20-item self-report rating scale designed to evaluate the frequency and severity of depressive symptoms and validated in French [START_REF] Fuhrer | La version française de l'échelle CES-D (Center for Epidemiologic Studies-Depression Scale)[END_REF][START_REF] Morin | Psychometric properties of the Center for Epidemiologic Studies Depression Scale (CES-D) in French clinical and nonclinical adults[END_REF]. Response to each item was on a 4-point scale varying from 0 to 3 and the total score ranged from 0 to 60. Participants with a CES-D score ≥16 are considered as having high levels of depressive symptomatology which would warrant clinical intervention (Radloff, 1977).

Baseline covariables

The standardized interview included questions on demographic characteristics, level of education and mode of living. Detailed medical questionnaires included history of diabetes and ischemic pathologies.

Participants with a body mass index (BMI) over 25 kg/m 2 were classified as overweight. At baseline and follow-up examinations, the general questionnaire included an inventory of all drugs (including antidepressant drugs) used during the preceding month which were systematically coded using the Anatomical Therapeutic Chemical (ATC) classification system (WHO Collaborating Centre, 2013).

Purpose of treatment was not recorded. Mobility was assessed according to the Rosow and Breslau scale (Rosow & Breslau, 1966) which evaluates ability to do heavy housework, walk half a mile, and climb stairs. Cognitive functioning was assessed using a modified version of the Isaacs Verbal Fluency test [START_REF] Isaacs | The Set test as an aid to the detection of dementia in old people[END_REF]. This timed test of lexical access draws on conceptual, linguistic and mnesic abilities, and is thus sensitive to pathologies in both frontal and posterior brain regions (Schlosser et al., 1998). The participants were asked to generate as many words as possible in 30 seconds within a given semantic category such as colors, animals, fruits or cities. In the absence of a validated cut-off, low cognitive performance was a priori defined in our study as scoring in the lower tertile and corresponded to a total score lower than 43.

A retrospective self-report questionnaire (Ritchie et al., 2009) examining traumatic experiences during childhood and adolescence (covering 25 adverse and 8 protective factors), was given to subjects for completion in the third wave of the study (four years after recruitment by which time the interviewer had established a close relationships with the participants). These factors were combined in three variables: parental mental problems, lack of support (less than 6 positive items among the following: paternal and maternal affection, availability of an adult friend, raised by both parents, impression of having had a happy childhood, a normal education, feeling happy at school and the impression that parents did their best) and adverse childhood events (at least one negative item among: poverty, neglected, verbal, physical or sexual abuse, humiliation or mental cruelty, excessive punishment, or parents too often sharing their problems with children). Exposure to stressful life events in the past year was also assessed at baseline using the Gospel Oak 12-item questionnaire including bereavement, rupture in a close relationship, severe illness and serious financial or legal problems [START_REF] Harwood | The prevalence of diagnoses, impairments, disabilities and handicaps in a population of elderly people living in a defined geographical area: the Gospel Oak project[END_REF]. The Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998), a standardized psychiatric examination was used for the diagnosis of past major depressive episodes, according to DSM-IV criteria.

Blood samples for DNA collection were taken after the baseline clinical interview. The serotonintransporter-promoter region (5-HTTLPR) was genotyped as previously reported (Ritchie et al., 2009) having previously been found to moderate the relationship between stress and depression [START_REF] Karg | The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation[END_REF][START_REF] Miller | The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis[END_REF].

Statistical analyses

The χ2 test for categorical variables and the Wilcoxon rank-sum test for continuous variables were used to identify gender differences and to compare the included and excluded participants. As the CES-D distribution is skewed to the left, the original scale was transformed with a beta cumulative distribution function simultaneously estimated with the LCMM model. The class-specific trajectories of depressive symptoms were described according to years since entry in the cohort using a quadratic polynomial without adjustment for baseline covariates. All analyses were stratified by gender. The optimal number of latent classes and the shape of the class-specific trajectories were determined by sequentially increasing the number of model parameters (one-to four-latent classes with a linear or quadratic time trajectory, a diagonal or unstructured random-effect covariance matrix and a class-specific or proportional random-effect covariance matrix (Proust-Lima et al., 2014)). This sequential procedure screened a total of 180 models for each gender (supplementary material). The Bayesian information criteria (BIC) were used to select the best model. For each model, fifty sets of random starting values were tested to ensure that an adequate solution was obtained.

Covariates were firstly introduced separately in the class-membership model adjusted for baseline age.

Significant covariates with a p-value <0.20 in the age-adjusted model were then put together in the multivariate models. Two nested adjusted models were built. The first (Model 1) included age, mobility, diabetes, obese or overweight and ischemic pathologies for both genders and also 5-HTTLPR genotype for men and cognitive performance for women. The second (Model 2) further included recent stressful life events as well as childhood lack of support, adverse events, and parental mental problems.

RESULTS

At baseline, the median age (IQR) of the 1253 participants (517 men and 736 women) was 72 years (68-76) and the median time (IQR) of follow-up was 8.9 (7.6-9.0) years. Women were more likely to live alone, have mobility restriction, and reporting parental mental problems during childhood (Table 1). They also reported more frequently high levels of depressive symptoms, antidepressant use and past major depressive episodes. Diabetes, ischemic pathologies, high BMI, and low cognitive performance were more frequent in men.

Trajectories of depressive symptoms

In both genders two sub-populations were identified corresponding to two different profiles of symptom change over the 10-year follow-up. The final mathematical expressions (supplementary material) of the estimated class-specific linear mixed models differed for men and women.

In men, both curves start at a low level of depressive symptoms (below the CES-D threshold of 16 at baseline). The upper curve (9.1% of men) increases over time with a marked quadratic shape at the end of the follow-up (Fig. 1A -solid curves). The confidence interval is large due to the relatively small number of subjects in this trajectory. The lower curve (90.9% of men) shows decreasing CES-D scores with a very low final level (5.2). In women, the upper curve (25.0% of women) shows a steady high level over the 10 years (mean CES-D at inclusion equal to 17.3) (Fig. 1B -solid curves) while the lower curve (75.0% of women) clearly decreases from 11.6 at the beginning to 5.4 at the end of the follow-up. The same patterns of symptom course were also found on the full sample of 1988 participants (816 men and 1172 women which included those with missing covariate data) (Fig. 1A and Fig. 1B -dashed curves), which further strengthens our results.

Of the 517 men and 736 women included in the main analysis, 57 men (11%) and 161 women (21.9%) were treated with antidepressant at least once over the 10-year follow-up. When trajectories of depressive symptoms were analyzed in the sub-group of treated women two trajectories with identical profiles were again found (Fig. 2), although they were shifted upwards in comparison with the overall sample. The group of treated men was too small to investigate their specific trajectories.

Factors associated with specific trajectories

In both genders the age-adjusted probability of being in the at risk upper trajectory was significantly increased with mobility limitations, diabetes, ischemic pathologies, recent stressful life event, parental mental problems, lack of support during childhood and past major depressive episode. Low cognitive performance and adverse childhood events in women and 5-HTTLPR genotype in men were also significant (Table 2). Baseline characteristics were then entered in the multivariate models with the exception of past major depressive episode and antidepressant use which may constitute intermediate factors between childhood events and depressive symptoms in late life.

In men, the odds of being in the upper increasing curve were higher when they had mobility limitations and diabetes with odds ratios of 3.98 and 3.10 respectively (Table 3, Model 1). The S allele of the 5-HTTLPR polymorphism tended to be negatively associated with the odds of a poor symptom course but the association did not reach the level of significance (p=0.09). When recent or adverse childhood events were further included in the model (Table 3, Model 2), mobility limitations, diabetes and ischemic pathologies as well as recent stressful events and marginally parental mental problem were associated with the upper curve. The association with 5-HTTLPR was no more significant and no significant interactions were found with recent or early childhood adverse environment (p-value >0.25).

In women, mobility limitations and ischemic pathologies were significantly associated with poor symptom course (Table 3, Model 1). When recent or adverse childhood events were further included in the model (Table 3, Model 2), these results remained unchanged. In addition, recent stressful events, adverse childhood events and parental mental problems were significant, with particularly high odds ratios for recent stressful events and adverse events during childhood (OR of 3.16 and 3.09, p≤0.0008).

DISCUSSION

Modeling symptom trajectories

Using 10-year follow-up data from a large general population cohort established specifically for the prospective study of psychiatric disorder in the elderly, we clearly differentiated pathways of chronic and remitting depressive symptoms for men and women. For a small group of men (9.1%), we observed an increase in depressive symptoms and a trend towards worsening at the end of the followup. A larger female group, comprising a quarter of women, was observed to have a constantly high level of symptoms (above the threshold of 16). In contrast to these two patterns showing persistent symptoms, the remaining majority of men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels. When the analysis was restricted to the women treated with antidepressants the same pattern was found with a sub-group showing a steady high level of symptoms, but this was higher than in overall sample which raises the question of treatment efficacy, adequacy and/or compliance.

Comparing our methodology with previous attempts to characterize depression trajectories in elderly population, past studies have mostly used a semi-parametric latent class growth analysis (LCGA) with the SAS procedure TRAJ [START_REF] Jones | Advances in group-based trajectory modelling and an SAS procedure for estimating them[END_REF]. This exploratory analysis is a specific case of LCMM in which the repeated measures within a subject are assumed to be independent. Applying the proc TRAJ to our data (data not shown) gives five trajectories in women and men. This overestimation of the number of latent classes is typical of LCGA [START_REF] Muthén | Growth mixture modeling: Analysis with non-Gaussian random effects[END_REF]. This may be explained by the neglected within subject correlation (modeled in the LCMM by subject-specific random-effects) which is captured by additional trajectory groups. A consequence of this is that inferences regarding covariates may be biased.

LCMM is similar to the Growth Mixture Modelling (GMM) implemented in M-Plus software [START_REF] Muthen | General growth mixture modeling for randomized preventive interventions[END_REF] with the exception that M-plus does not normalize the scores using parameterized transformations. Using this methodology with a modified CES-D scale ranging from 0 to 20 [START_REF] Kuchibhatla | Trajectory classes of depressive symptoms in a community sample of older adults[END_REF], Kuchibhatla et al found four groups of trajectories (stable high, stable low, increasing and decreasing). The study was not, however, stratified by gender although in the final multinomial logistic model, female gender was reported to be associated with the downward and stable high trajectories; this being consistent with our findings.

Risk factors for chronic trajectories in men and women

Examining a large range of covariates commonly associated with depression in the elderly across the life-span, we observed that a chronic course was associated with both distal and proximal risk factors.

With regard to early-life factors, having reported parents with psychiatric disorders and adverse events during childhood in women, were significantly associated with a severe and chronic course of illness in late life. Adverse childhood experiences are associated with later affective vulnerability [START_REF] Chapman | Adverse childhood experiences and the risk of depressive disorders in adulthood[END_REF]. Possible explanations of this association could involve a genetic pathway (particularly when parents had mental problems), early structural and functional changes of the nervous system (functional changes of corticotropic hypothalamic-pituitary-adrenal axis and alterations in brain structures like the hippocampus) [START_REF] Frodl | How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans[END_REF], stress related inflammation and metabolic dysfunctions (Vamosi et al., 2010) as well as epigenetic changes [START_REF] Klengel | The role of DNA methylation in stress-related psychiatric disorders[END_REF] and telomere shortening [START_REF] Kiecolt-Glaser | Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation[END_REF]. In the same cohort, we previously reported an association between past traumatic life event and alteration in metabolic or vascular disorders [START_REF] Chaudieu | Late-life health consequences of exposure to trauma in a general elderly population: the mediating role of reexperiencing posttraumatic symptoms[END_REF] as well as cortisol secretion [START_REF] Chaudieu | Abnormal reactions to environmental stress in elderly persons with anxiety disorders: evidence from a population study of diurnal cortisol changes[END_REF] and a permanent alteration in hypothalamicpituitary-adrenal axis in the participants with a history of depression [START_REF] Beluche | Persistence of abnormal cortisol levels in elderly persons after recovery from major depression[END_REF]. Our results remained significant in women despite possible over-adjustment on intermediate factors (obesity, diabetes, ischemic pathologies, and recent stressful events). In men, the associations with parental mental problems and lack of support during childhood became non significant after multiple adjustment but this may be due to lack of statistical power and/or possible over-adjustment. While previous research has shown that adverse childhood exposures may induce on-going vulnerability to depression persisting into late-life (Ritchie et al., 2009) we further extend these findings by suggesting they also contribute to depressive symptom chronicity.

Vulnerability to depression following adverse childhood exposures has been observed to be modulated by 5-HTTLPR polymorphism, with carriers of the short (S) allele having increased risk although not consistently [START_REF] Karg | The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation[END_REF]Risch et al., 2009). The reverse risk has been also observed, with carriers of the L allele being more vulnerable, and this has been related to insecure attachment, family adversity, and lower resilience capacity in younger [START_REF] Carli | A protective genetic variant for adverse environments? The role of childhood traumas and serotonin transporter gene on resilience and depressive severity in a high-risk population[END_REF][START_REF] Laucht | Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults[END_REF]Olsson et al., 2005) as well as in older populations (Ritchie et al., 2009;Surtees et al., 2006). We only found a weak association in men with the S allele being protective which disappeared after adjustment for early adverse events including parental risk.

With regard to more proximal risk factors, we found very recent stressful events (disease, death, divorce and financial and judicial problems in the past year) to be associated with adverse trajectories in men and women in the multivariate model independently of early adverse environment. Only one previous trajectory study [START_REF] Kuchibhatla | Trajectory classes of depressive symptoms in a community sample of older adults[END_REF] also found recent stressful life events to be a risk factor for chronic course. In relation to other proximal factors we found mobility limitations and ischemic pathologies in men and women, as well as diabetes in men to be linked to adverse trajectories.

Diabetes, heart disease and global burden of chronic diseases were associated with a high risk of developing depression in other trajectory studies [START_REF] Byers | Twenty-year depressive trajectories among older women[END_REF][START_REF] Chen | Trajectories of depression and their relationship with health status and social service use[END_REF]. Depression has consistently been associated with vascular risk including ischemia and diabetes, it is present in around 20% of patients with cardiovascular disease and in 18-39% of type 2 diabetic patients (Roy & Lloyd, 2012) and is associated with adverse cardiovascular outcomes (Rudisch & Nemeroff, 2003). A number of biological mechanisms (neuroendocrine dysfunction, hemodynamic factors, immune activation, thrombotic predisposition) (Parissis et al., 2007) and behavioral factors (smoking, obesity, poor self-care) [START_REF] Joynt | Depression and cardiovascular disease: mechanisms of interaction[END_REF] can link depression and cardiovascular disease in a bidirectional relationship. In diabetic patients, specific risk factors such as diabetes complications, poor glycemic control, and burden of insulin therapy can also increase the risk of depression (Renn et al., 2011). In our study the risk increase associated with ischemic pathologies persisted after multiple adjustments while that association with diabetes persisted only in men. Icks et al also found no significant association between diabetes and depressive symptoms in women after controlling for co-morbidities [START_REF] Icks | Are symptoms of depression more common in diabetes? Results from the Heinz Nixdorf Recall study[END_REF].

In women poor cognitive performance in verbal fluency was also at risk in the age-adjusted model. However, this association became non significant after controlling for physical comorbidity and mobility limitations. Three trajectory studies in the elderly failed to demonstrate a significant association between cognitive performance evaluated with the Mini Mental State Examination or the Trail Making Test and unfavorable trajectories [START_REF] Andreescu | Twelve-year depressive symptom trajectories and their predictors in a community sample of older adults[END_REF][START_REF] Byers | Twenty-year depressive trajectories among older women[END_REF][START_REF] Cui | Outcomes and predictors of late-life depression trajectories in older primary care patients[END_REF]. Only one study showed that poor mental status measured with the Short Portable Mental Status Questionnaire (a very brief dementia screening test) increased the odds of being in the worsening symptom class [START_REF] Kuchibhatla | Trajectory classes of depressive symptoms in a community sample of older adults[END_REF]. Depressive symptoms may be a reaction to early cognitive deficit, chronic depression may impair cognitive functions, and depression may be a risk factor or a prodromal stage of dementia for a subset of older adults [START_REF] Byers | Depression and risk of developing dementia[END_REF].

Our results indicate that mobility limitation is a highly significant risk factor for chronic symtomatology in both men and women with a 4-5-fold increase in the odds of being in the increasing symptoms class or in the chronic but stable high symptom class, respectively. Activities of daily living or physical functioning were also found to predict poor outcome in previous studies of the course of depressive symptoms [START_REF] Andreescu | Twelve-year depressive symptom trajectories and their predictors in a community sample of older adults[END_REF][START_REF] Byers | Twenty-year depressive trajectories among older women[END_REF][START_REF] Chen | Trajectories of depression and their relationship with health status and social service use[END_REF][START_REF] Cui | Outcomes and predictors of late-life depression trajectories in older primary care patients[END_REF][START_REF] Hsu | Group-based trajectories of depressive symptoms and the predictors in the older population[END_REF][START_REF] Kuchibhatla | Trajectory classes of depressive symptoms in a community sample of older adults[END_REF][START_REF] Liang | Multiple trajectories of depressive symptoms in middle and late life: racial/ethnic variations[END_REF]. A range of mediators have been suggested to explain the association between disability and the development of depression, notably decreased selfesteem, loss of sense of control, restriction of the social network, and isolation [START_REF] Carriere | Modelling complex pathways between late-life depression and disability: evidence for mediating and moderating factors[END_REF].

Altogether, our study highlighted distinct baseline thresholds of CES-D scores in elderly women and men which predict future adverse trajectories; the upper trajectory initiated at in women and slightly lower in men, at 13.2 (95%CI: 10.4-16.4), and these baseline levels were significantly higher from those of the remitting trajectories (Fig. 1). Our study also enabled the characterization of risk factors for a poor course of depressive symptoms in the elderly. This may help to detect elderly people who could benefit from an early intervention, thus preventing them from latelife depression and subsequent consequences in terms of co-morbidity and functional disability.

Limits and strengths

Our study has several limitations. Although repeated examinations have been performed with five time points over 10 years, between-wave transitory changes in depressive symptoms may not have been detected. As in all other trajectory studies, the effect of missing data and study attrition was not addressed in this study. Our statistical models assumed such effects to be negligible (ignorable missing response assumption [START_REF] Little | Statistical Analysis with Missing Data[END_REF]) however a possible link may exist between loss to follow-up and worsening of depressive symptoms which may have affected trajectory estimates. Since the depressive trajectory groups were different on baseline depressive symptoms, the relationships between risk factors and depressive symptom trajectories could be partly due to associations with baseline depressive levels. The two worst trajectories included 25% women and only 9.1% men which suggests lower statistical power and lack of statistical significance for some exposures in men.

Furthermore stratifying analyses by gender precluded drawing conclusions with regard to gender difference in risk factors. Finally information based on retrospective recall, especially for childhood events, could not be independently validated; however, the observed associations were very strong.

Our study presents several strengths. We used a robust statistical method taking into account the highly skewed distribution of the CES-D scale with the beta distribution function and within-subject correlation with subject-specific random effects. We checked that the profiles of symptom course were the same in the whole original sample and in the restricted sample without missing data for covariates.

We used data over ten years from a prospective general population study specifically designed to examine the course of psychiatric symptomatology in the elderly. We used a symptom scale with a wide score range and examined a wide range of depression-related risk factors including for the first time, early life exposures and genetic factors. We stratified by gender in order to observe genderspecific course and risk factors of depressive symptoms.

In conclusion, the analyses suggest for the first time distinct patterns of chronic and remitting symptomatology course in men and women and that a chronic disease course is associated with exposure to recent life stressors, disability and disease co-morbidity in both genders as well as to childhood adversity in women.

  The latent class mixed model (LCMM) was used to identify trajectory groups of CES-D score over time. This model seeks potential latent profiles in heterogeneous populations. It combines a latent class model to identify homogenous latent groups of subjects and a mixed model to describe the mean trajectory over time in each latent group, while taking into account the individual correlation between repeated measures. In the latent class submodel, a multinomial logistic model was used to characterize the latent classes according to baseline covariates. The function LCMM (Proust-Lima et al., 2014) of the R-package version 3.1.3 was used to estimate the model parameters.

Fig

  Fig. 1 Depressive symptom trajectories in men and women 1A: Men

Fig. 2

 2 Fig. 2 Depressive symptom trajectories in women treated with antidepressant

TABLE 1 .

 1 Sample description at baseline (n=1253) : body mass index, IQR: inter quartile range, CES-D: Center for Epidemiologic Studies Depression Scale

	Men	Women	P-value
	n=517	n=736	Chi 2 test

e History of stroke, myocardial infarction, angina pectoris, arteritis, or cardio-vascular surgery f Isaacs Verbal Fluency test score at 30 seconds < 43 BMI

TABLE 2 . ASSOCIATIONS BETWEEN BASELINE COVARIATES AND THE PROBABILITY OF BEING IN THE UPPER TRAJECTORY -AGE ADJUSTED CLASS-MEMBERSHIP MODELS

 2

		Men		Women
		N=517		N=736
		OR [95%CI]	p value	OR [95%CI]	p value
	Educational level ≤ 5 years	0.89 [0.31;2.62]	0.84	0.87 [0.48;1.56]	0.63
	Living alone	1.80 [0.53;6.10]	0.34	1.04 [0.63;1.74]	0.87
	Mobility limitations	4.45 [1.79;11.02]	0.001	5.28 [1.88;14.79]	0.002
	Diabetes	3.74 [1.37;10.26]	0.01	2.80 [1.18;6.63]	0.02
	BMI: obese or over-weighted	1.99 [0.81;4.88]	0.13	1.52 [0.94;2.47]	0.09
	Ischemic pathologies	2.81 [1.19;6.62]	0.02	3.20 [1.41;7.23]	0.005
	5-HTTLPR polymorphism, S allele	0.46 [0.21;1.00]	0.05	0.74 [0.45;1.22]	0.23
	Cognitive impairment	1.05 [0.45;2.46]	0.91	1.85 [1.06;3.21]	0.03
	Recent stressful life event	3.25 [1.02;10.33]	0.05	2.60 [1.40;4.84]	0.002
	Adverse childhood event	1.95 [0.88;4.30]	0.10	3.75 [2.23;6.31]	<0.0001
	Parental mental problems	2.95 [1.21;7.20]	0.02	2.55 [1.43;4.53]	0.002
	Lack of support during childhood	3.03 [1.12;8.22]	0.03	2.47 [1.30;4.68]	0.006
	Past major depressive episode	12.81 [4.00;40.96]	<0.0001	4.21 [2.27;7.80]	<0.0001

OR: Odds ratio; CI: Confidence Interval, BMI: Body mass index

Table 3 . ASSOCIATIONS BETWEEN BASELINE COVARIATES AND THE PROBABILITY OF BEING IN THE UPPER TRAJECTORY-MULTIVARIATE CLASS-MEMBERSHIP MODELS

 3 Odds ratio; CI: Confidence Interval, BMI: Body mass index

		Model 1		Model 2
		OR [95%CI]	p value	OR [95%CI]	p value
	MEN, N=517
	Age (years)	1.07 [0.98;1.16]	0.13	1.07 [0.97;1.17]	0.16
	Mobility limitations	3.98 [1.54;10.28]	0.004	4.48 [1.56;12.87]	0.005
	Diabetes	3.10 [1.09;8.77]	0.03	3.50 [1.13;10.87]	0.03
	BMI: obese or over-weighted	1.37 [0.56;3.36]	0.49	1.11 [0.43;2.87]	0.83
	Ischemic pathologies	2.01 [0.79;5.10]	0.14	2.91 [1.03;8.26]	0.04
	5-HTTLPR polymorphism: S allele	0.46 [0.19;1.13]	0.09	0.63 [0.24;1.65]	0.35
	Recent stressful life event			4.50 [1.09;18.50]	0.04
	Adverse childhood event			1.39 [0.49;3.93]	0.53
	Parental mental problems			2.96 [0.88;9.93]	0.08
	Lack of support during childhood			2.48 [0.81;7.59]	0.11
	WOMEN, n=736
	Age (years)	1.00 [0.96;1.04]	0.99	1.02 [0.96;1.08]	0.59
	Mobility limitations	4.54 [2.23;9.24]	<0.0001	4.95 [2.30;10.68]	<0.0001
	Diabetes	2.16 [0.79;5.94]	0.13	2.24 [0.71;7.03]	0.17
	BMI: obese or over-weighted	0.97 [0.56;1.68]	0.91	0.87 [0.47;1.63]	0.67
	Ischemic pathologies	3.06 [1.11;8.38]	0.03	3.14 [1.00;9.86]	0.05
	Cognitive impairment	1.60 [0.86;2.97]	0.14	1.47 [0.77;2.83]	0.25
	Recent stressful life event			3.16 [1.62;6.17]	0.0008
	Adverse childhood event			3.09 [1.64;5.81]	0.0005
	Parental mental problems			2.52 [1.15;5.52]	0.02
	Lack of support during childhood			1.57 [0.72;3.41]	0.25
	OR:

Financial support

The 3C Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (Inserm), Victor-Segalen Bordeaux2 University, and Sanofi-Aventis. The 3C-Study was also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, the Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Regional Governments of Aquitaine, Bourgogne and Languedoc-Roussillon, the Fondation de France, the Ministry of Research-Inserm Programme 'Cohorts and collection of biological material', Novartis, the "ANR -Agence Nationale de la Recherche -The French National Research Agency" under the "Programme National de Recherche en Alimentation et nutrition humaine", project "COGINUT ANR-06-PNRA-005", the "Programme Longévité et vieillissement", project 07-LVIE-004" and 07-LVIE 003 01, the Institut de Recherche en Santé Publique (IReSP), Paris, France.

The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Conflict of interest:

None

Olsson CA, Byrnes GB, Lotfi-Miri M, Collins V, Williamson R, Patton C, Anney RJ (2005). Association between 5-HTTLPR genotypes and persisting patterns of anxiety and alcohol use: results from a 10-year longitudinal study of adolescent mental health. Molecular Psychiatry 10, 868-76. Parissis JT, Fountoulaki K, Filippatos G, Adamopoulos S, Paraskevaidis I, Kremastinos D (2007) Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301, 2462-71.


Yohann Dabi

Lauren Darrigues

Sandrine Katsahian

Daniel Azoulay

Marie De Antonio

Andrea Lazzati
email: andrea.lazzati@chicreteil.fr

Dabi Yohann

Darrigues Lauren

Marie De

Andréa Lazzati

Andrea Mr

MD Lazzati

Trends in Bariatric Surgery: a Bibliometric Study

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

The last two decades have seen an exponential growth in bariatric surgery [START_REF] Buchwald | Metabolic/bariatric surgery worldwide 2011[END_REF]. Several studies have described national trends in Europe [START_REF] Burns | Introduction of laparoscopic bariatric surgery in England: observational population cohort study[END_REF][START_REF] Stroh | A nationwide survey on bariatric surgery in Germany-results 2005-2007[END_REF][START_REF] Marsk | Antiobesity surgery in Sweden from 1980 to 2005: a population-based study with a focus on mortality[END_REF][START_REF] Lazzati | Bariatric surgery trends in France: 2005-2011[END_REF], North America [6] and Asia [START_REF] Lomanto | Bariatric surgery in Asia in the 598 last 5 years (2005-2009)[END_REF]. Similarly, the interest of researchers in this field has been rapidly increasing. Some authors have previously reported an important increase in the number of publications on obesity with more than 50,000 references retrieved [START_REF] Vioque | A bibliometric study of scientific literature on obesity research in PubMed (1988-2007[END_REF]. Nevertheless, little is known about scientific production in bariatric surgery, and, to our knowledge, no bibliometric analysis in this field has been published.

Bibliometrics is defined as the application of statistics and mathematics for the analysis of written publications such as books and journal articles [START_REF] Pritchard | Statistical Bibliography or Bibliometrics?[END_REF]. Bibliometrics methods can be used to provide the analysis of scientific literature in a specific field in order to assess the popularity and the impact of specific publications, authors and institutions. It also permits the description of scientific networking through the analysis of relationships between academic journal citations. Several bibliometric indicators and laws are currently used to analyze the behavior of scientific production. The founding hypothesis of bibliometrics is that bibliometric indicators and scientific networks represent a mirror image of scientific activity. Thus, a bibliometric analysis of publications in bariatric surgery could outline the characteristics of research in this domain.

The aim of this study was to give an overview on scientific production in bariatric surgery with a focus over the period 2010-2014.

METHODS

Data source

The database used for data selection was Web of Science (WoS). The search strategy included the keywords "Bariatric surgery" and "Obesity surgery" with "or" as Boolean term. Only original articles and reviews published in English were retrieved. Data extraction was performed on 20 July 2015.

Economic and demographic data were collected from the World Bank database [10]. This included number of inhabitants, gross domestic product (GDP) per capita, health total expenditure and research and development total expenditure (R&D). Obesity prevalence across the world was extracted from the World Health Organization (WHO) database [START_REF]Global Database on Body Mass Index[END_REF]. Data were available for the years 2008 and 2013. The impact factor (IF) and the 5-year impact factor (5y-IF) of a journal were issued from the Journal Citation Reports (JCR) in 2015.

In order to assess knowledge of the English language, we used the English First Proficiency Index (EF EPI), 2011-2014, published by EF Education First, a global language training company. The EF EPI is a score that ranks countries by the average level of English skills amongst adults. Data are collected via an English test available on the Internet. The most recent edition, released in November 2014, was compiled using test data from 750,000 test takers. In order to be included, a country was required to have at least 400 test takers in total [START_REF]Methodology[END_REF][START_REF]EF English Proficiency Index[END_REF]. The EF score was imputed to the maximum value for Native English countries.

Bibliometric indicators

Our analysis is based upon a series of bibliometric indicators and laws considered as referential.

Overall productivity

In order to evaluate the overall growth of scientific production in bariatric surgery we tested Price's law [START_REF] Price | Little science, big science[END_REF]. This law is probably the most common bibliometric indicator for analyzing the productivity of a specific discipline. The main hypothesis of this law is that the development of science follows an exponential growth. More exactly, the growth of a scientific domain goes through four phases. The first is called the precursors' phase, where a small body of scientists begins publishing on a new field.

The second phase is the proper exponential growth, when the expansion of the field attracts an increasing number of scientists, as many aspects of the subject still have to be explored. In the third phase, we observe a consolidation of the body of knowledge, which is followed by a decrease in the number of publications. The growth of scientific production becomes linear, so, ultimately, the aspect of the curve transforms from exponential to logistic. The fourth phase corresponds to the collapse of the domain and the important reduction of publication. Furthermore, Price suggests that science production develops at a faster pace than other human activities, duplicating its size every 10-15 years [START_REF] Price | Science since Babylon[END_REF]. Nevertheless, the time of duplication is not the same in all scientific fields, as some disciplines grow faster than others, suggesting that science is not a homogenous bloc.

Authors' activity

Lotka's law [START_REF] Lotka | The frequency distribution of scientific productivity[END_REF] studies the relation between the number of authors and the number of publications.

It supposes that the author-article relation is inversely proportional to the square of published articles.

The number of scientific authors who write i articles is equal to: 𝑛 𝑖 = 𝑛 1 /𝑖 2 , where 𝑖 = 1,2,3, … 𝑖 𝑚𝑎𝑥 (𝑖 𝑚𝑎𝑥 being the maximum productivity of an author) and 𝑛 1 is the number of scientists who wrote one article ("single paper authors"). Lotka's law follows a hyperbolic distribution, meaning that a large number of researchers publish a few articles (heart of the curve) and a few publish many (dispersion of the curve). If the hyperbolic distribution of Lotka's law is generally accepted, the exponent of the denominator is not always equal to two, as it can change from one domain to another.

Journals' activity

Bradford's law was used to evaluate the dispersion of information among scientific journals. According to this law, journals are sorted into zones of decreasing productivity, based on their proportion of articles on the topic. Each zone would contain the same number of articles, but the number of journals implied would increase moving from one zone to another. The first zone represents the most used or specific journals in bariatric surgery.

The impact factor (IF) is a measure reflecting the average number of citations on recent articles published in a journal. The IF for a given year is based on the ratio of total citations obtained in the previous two years over the number of articles they published in the same two years. The IF is the actual measure for ranking journals inside a specific scientific category. We specifically considered the 5-year impact factor of prolific journals, which is an average of the annual impact factor for the period studied.

Extraction per journal was used to rank the most prolific newspapers regarding bariatric surgery and then to calculate their participation index (PAI). Participation index represents the portion of scientific production of a journal in a specific field of interest with respect to global production in this field over the period.

Countries' activity

In order to assess the contribution of different countries to the scientific production, we adjusted the number of publications per country to the number of inhabitants (number of publications per million inhabitants). We then correlated this measure with several demographic and economic factors: the GDP per capita, Health total expenditure, Research and Development total expenditure, the prevalence of obesity and the EF Proficiency Index.

Our bibliographic research (with the aforementioned criteria) retrieved a first article from 1973. Therefore Price's law was assessed over the period 1973-2014. All other bibliometric indicators focused on the period 2010-2014.

Statistical analysis

Quantitative variables are described by their means (sd) and qualitative variables are described by N (%). Number of publications distribution and its log transformation were summarized by a linear univariate regression and a Pearson correlation coefficient to assess the relationship over the time. If the log distribution fits better than initial data with the time, the trend is exponential according to Price's law. Expected distribution is predicted with coefficients from linear univariate regression. In Lotka's graph, expected distribution is calculated by Lotka's formula: 𝑛 𝑖 = 𝑛 1 /𝑖 2 with n the number of authors and i the number of publications. To fit with the observed distribution, we adjust the Lotka's distribution by changing the exponent: 𝑛 𝑖 = 𝑛 1 /𝑖 𝑥 (x=2 in Lotka's law). The exponent x is estimated by the mean of the observed x: 𝑥 = ln (𝑛 1 /𝑛 𝑖 )/ ln(𝑖).

Regression imputation is used to replace missing data over the time. In case of data available only a single year we suppose a non-evolution. Several transformations were tested on the number of publications per habitants. Fourth root transformation distribution seems to fit well with a normal distribution. We have repeated measurements over time (from 2010 to 2014), so we use mixed model with a random slope which varying among country. Univariate and multivariate mixed model regression is performed to explain the number of publications per habitants.

All statistical analyses were performed using the R (R Foundation for Statistical Computing, Vienna, Austria. ), package "nlme" and for all tests, significant level is set to 5%.

RESULTS

Bibliographic research retrieved a total of 15,260 papers from 1973 to 2014, and 7,860 for the period 2010-2014. As Figure 1 shows, we observed a significant increase in the number of publications in bariatric surgery during the study period. After adjustment to an exponential curve, we obtain a correlation coefficient r of 98.0%, indicating that 4.08% of variability is not explained by the adjustment. On the contrary, with a linear adjustment of the curve, the r coefficient is 82.3%, which means that the percentage of unexplained variability is 33.1%. These data confirm that the scientific production in bariatric surgery is closer to an exponential adjustment than a linear adjustment, as predicted by Price's law. With regard to the different phases of the law, we observe the first one (the precursors' phase) up to the beginning of the nineties. We then observe a progressive increase in the number of publications until 2013, corresponding to the second phase of exponential growth. A slightly lower increase is observed in 2014. During the exponential growth the time of duplication of the number of publications was between 3 and 6 years.

Lotka

Authors' productivity is presented in Figure 2. A total of 28,505 authors published on bariatric surgery between 2010 and 2014. Among these, 21,893 (76.8%) signed one paper, and 6,305 (22.1%) signed between 2 and 9 papers. We observed 307 (1.1%) authors signing at least 10 publications over the period studied (i.e. on average: 2 papers per year for 5 years). The distribution of the number of publications per author has a hyperbolic aspect, according to Lotka's law. Nevertheless, the observed distribution deviates from the expected distribution on the right side of the graph, corresponding to the zone of high-productivity authors. Lotka's law seems to overestimate these authors. The exponent of the denominator of the formula n i = n 1 /i 2 is 2.4 for the observed distribution.

Bradford

The 20 most prolific journals in bariatric surgery are listed in Table 1, with their respective 5-year IF, quartile rank, Participation Index and category. The two most prolific are Obesity Surgery and Surgery For Obesity And Related Diseases (SOARD), which are surgical journals sub-specialized in the bariatric field. Nevertheless, these two journals published only 21.9% of bariatric papers in the study period.

The mean IF is 3.70, ranging from 1.17 to 8.84. Most of the journals (13/20, 55%) rank in the first quartile of their category. Remarkably, 60% (12/20) of journals publishing on bariatric surgery are surgical, with the remaining (8/20, 40%) belonging to medical fields such as endocrinology and nutrition.

The distribution of journals into Bradford's zones is presented in Table 2. Data are presented for the years 2010 and 2014 and the mean for the entire study period. Bradford's zone 1 corresponds to journals publishing 25% of papers. In 2010, 2 journals were in zone 1 (Obesity Surgery and SOARD), while there were 4 in 2014 (Obesity Surgery, SOARD, Surgical Endoscopy and PLOS ONE). The total number of journals publishing on bariatric surgery has increased by 39.2%, rising from 453 to 631.

National activity

Table 3 presents the number of publications per country during the period 2010-2014. The number of articles is adjusted per number of inhabitants, GDP per capita, health total expenditure, R&D total expenditure and prevalence of obesity. The USA produces the highest number of publications (N=2980), followed by the United Kingdom (n=554) and Italy (n=399). After adjustment for the number of inhabitants, Sweden, Norway and Switzerland are the most prolific nations, and are also at the top of the ranking for the number of articles per obese population. Data per continent are presented at the bottom of the table. North America and Europe have a similar profile in scientific production in the bariatric field: 3,282 and 3,180 publications in the study period, which makes a mean of 1.82 and 1.56 papers per million inhabitants, respectively.

The results of univariate and multivariate analysis for the association between the number of publications and the aforementioned covariates are presented in Table 4. We observe that Health total expenditure and obesity prevalence are the 2 factors with the strongest association with the Number of articles. English proficiency and R&D total expenditure are not significantly associated with the number of publications in multivariate analysis.

DISCUSSION:

This study outlines the profile and the trends of scientific production in bariatric surgery over the period 2010-2014. First, we observed an exponential increase in the number of publications over the study period. The distribution of this growth shows a first phase of slow progression (corresponding to Price's phase 1, the "precursors' phase") up to the beginning of the nineties. We suggest that two major events probably helped the acceleration of the number of publications at that time: the creation of the first journal specialized in bariatric surgery (Obesity Surgery, first issue March 1991) and the rapid diffusion of laparoscopy. In fact, the number of articles published on laparoscopy went from 65 in 1990 to 504 in 1994. The second phase of Price's law, the real exponential growth, begins around 1991-1993. This phase corresponds to the period where the discipline is still a terra incognita of science. The number of researchers increases constantly, and the progression of knowledge opens new fields of interest. Furthermore, the exponential increase of publications presents a time of duplication of between 3 and 6 years, which is almost three times faster than predicted by Price's law.

Nevertheless, since 2010 the number of publications is lower than expected with an exponential distribution. Probably bariatric surgery is entering the third phase of Price's law, where the growth of the number of publications shifts from exponential to linear. The third phase corresponds to the consolidation of knowledge of a domain becoming familiar, where the number of researchers remains steady, and some subfields of research are cut off and lose interest [START_REF] Price | Quantitative Measures of Development of[END_REF]. If the publication trend is really shifting to linear, we'll observe around 2,050 articles in 2015 and 2,150 in 2016.

With regard to the number of publications per author, the observed distribution is hyperbolic according to Lotka's law. Nevertheless, the curve deviates from the expected distribution in the right part of the graph corresponding to prolific authors. Indeed, if the aspect of the curve is not discussed, the formula remains debated [START_REF] Radhakrishnan | Lotka's Law and Computer Science Literature[END_REF][START_REF] Voos | Lotka and information science[END_REF]. In particular, some authors believe that the formula proposed by Lotka overestimates prolific authors [START_REF] Price | Science et Suprascience. Traduction française de G. Lévy[END_REF], as the exponent of the denominator in the formula 𝑛 𝑖 =𝑛 1 /𝑖 2 is probably higher than 2. Rostaing [START_REF] Rostaing | Veille technologique et bibliométrie : concepts, outils[END_REF] suggests that the exponent depends on the field of study, showing that, for instance, the distribution of pharmacological and electronic patents has an exponent of 2.71 and 3.04, respectively. Hence, a more general formula of the equation would rather be 𝑛 𝑖 =𝑛 1 /𝑖 (1+𝑎) , with the coefficient 𝑎 depending on the field of study. In our case, we found an exponent of 2.4. The number of authors publishing on average 2 publications per year for 5 years was 307 (1.1%). Consequently we could assert that bariatric surgery is a field with few active researchers and many occasional writers.

The most prolific journals (Bradford zone 1, accounting for 25% of publications) went from 2 in 2010 to 4 in 2014. Not surprisingly, Obesity Surgery and SOARD, the two sub-specialized surgical revues in this field, are the most prolific. Nevertheless, we observed a growing interest in bariatric surgery among other revues, in particular non-surgical ones. The metabolic effect of weight loss may explain the interest of medical journals in this surgical discipline. Hence, our analysis can help specialists concerned with bariatric surgery to identify the most relevant journals among a large panel.

North America and Europe are the world's leading areas in scientific production on obesity. Despite a lower number of total publications, the Pacific area (Australia and New Zealand), after adjustment, has a profile very close to that of Europe and North America. Not surprisingly, the USA publishes the greatest absolute number of studies. Interestingly, after adjustment for total population and obese population, Sweden, Norway and Switzerland produce more scientific research than other countries.

Vioque et al. [START_REF] Vioque | A bibliometric study of scientific literature on obesity research in PubMed (1988-2007[END_REF] have already reported the important contribution of Scandinavian countries in obesity research [START_REF] Lomanto | Bariatric surgery in Asia in the 598 last 5 years (2005-2009)[END_REF]. With regard to the adjustment for economic factors (GDP per capita, health total expenditure and R&D total expenditure), the most effective countries are Greece, Israel and Kuwait.

Multivariate analysis shows that several factors are related to the number of publications in bariatric surgery. Health total expenditure presents the strongest association, suggesting that the amount of resources allocated to health is associated with scientific production. Inversely, R&D expenditure and English proficiency are not statistically significant.

This study presents several limitations. First, although the keywords we used for our search ("obesity surgery" and "bariatric surgery") seem logical and pertinent, the search was not exhaustive. We observed a lack of completeness, especially for the oldest articles (the first one identified by our search criteria was published in 1973). We think that the 2 keywords "obesity surgery" and "bariatric surgery" do not identify exhaustively the oldest publications because these terms become relevant for this discipline with time. Nevertheless, this limitation concerns only the indicator of overall growth of publications (Price's law), which shows that up to the nineties, publications in bariatric surgery were limited. Second, we decided to limit our search to English language literature because most relevant journals are published in English. In addition, our analysis suggests that English proficiency is not associated with the number of publications per country. This means that the degree of knowledge of the English language is not a limitation or an enhancement for publishing in English revues.

Finally, our analysis is essentially quantitative as the indicators we used are based on the number of publications (per year, per author, per journal and per country). No qualitative analysis was performed on the retrieved articles. A qualitative analysis would adjust the number of publications with their scientific impact, based on the number of citations for any single article. This is undoubtedly an interesting field for further studies.

CONCLUSION FIGURES LEGEND

Figure 1 .

 1 Figure 1. Number of publication on bariatric surgery per year: observed and expected distribution

Figure 2 .

 2 Figure 2. Number of publication on bariatric surgery per author: observed and expected distribution

$

  Number of publications per 1000$ of Gross Domestic Product per capita. € Number of publications per 1000$ of Health expenditure per capita. £ Number of publications per 1000$ of Research and Development expenditure per capita. # Number of publications per million obese population.

TABLES Table 1 .

 TABLES1 Most prolific journals in bariatric surgery, 2010-2014

Table 3 .

 3 Number of publications in bariatric surgery, 2010-2014, and adjustments per socioeconomic factor

	COUNTRY	Total	per inhabitant*	No. of publications per GDP $ per Health expenditure €	per R&D expenditure £	per Obesity prevalence #	English proficiency
	USA	2980	1.9	36.92	2.11	13.42	5.75	70
	UNITED KINGDOM	554	1.74	41.81	4.5	24.31	6.99	70
	ITALY	399	1.33	37.05	4.04	28.9	6.84	51.28
	CANADA	302	1.74	34.03	3.11	19.38	7.6	70
	GERMANY	297	0.73	16.24	1.43	5.57	2.99	58.46
	BRAZIL	290	0.29	24.14	2.58	19.69	1.73	48
	FRANCE	290	0.88	21	1.8	9.31	4.49	52.9
	SPAIN	272	1.17	38.4	4.15	29.14	5.21	52.8
	AUSTRALIA	239	2.11	33.85	3.67	14.15	7.42	70
	SWEDEN	180	3.79	65.79	6.85	19.85	19.57	67.68
	NETHERLANDS	164	1.96	38.44	3.08	18.86	12.76	67.2
	PEOPLE'S R CHINA	158	0.02	3.77	0.7	1.91	0.66	48.9
	SWITZERLAND	133	3.33	39.63	3.51	15.65	18.6	56.4
	JAPAN	132	0.21	4.91	0.49	1.47	5.59	54.14
	POLAND	99	0.52	38.6	5.72	45.52	2.42	58.44
	SOUTH KOREA	99	0.4	15.9	2.17	3.9	6.09	54.36
	BELGIUM	98	1.77	38.14	3.51	17.06	8.03	59.48
	TAIWAN	98	0.84	41.41	6	13.8	4.97	34.76
	GREECE	89	1.6	67.38	7.13	93.32	7.98	NA
	TURKEY	89	0.24	22.69	3.76	25.5	0.89	45.12
	AUSTRIA	87	2.07	41.85	3.71	14.82	10.48	60.92
	NORWAY	87	3.48	35.51	3.73	21.06	18.12	66.34
	DENMARK	82	2.93	49.3	4.53	16.37	14.91	67
	ISRAEL	81	2.05	60.49	8.16	15.64	8.57	NA
	FINLAND	72	2.67	54.76	5.96	15.24	12.31	62.76
	IRELAND	66	2.87	56.94	6.56	32.5	12.11	70
	CHILE	62	0.71	48.87	6.63	117.47	2.62	46.88
	INDIA	51	0.01	5.5	1.39	6.82	0.24	52.42
	PORTUGAL	39	0.74	33.77	3.44	32.04	3.18	55.24
	NEW ZEALAND	34	1.55	38.83	3.86	30.72	5.35	70
	MEXICO	32	0.05	5.41	0.88	12.18	0.19	50.14
	CZECH REPUBLIC	30	0.57	28.43	3.83	16.08	2.37	54.82
	SINGAPORE	29	1.09	20.53	4.56	10.22	17.06	58.58
	EGYPT	27	0.07	20.91	4.18	45.26	0.19	47.52
	SAUDI ARABIA	27	0.19	7.92	2.37	60.91	0.55	44.78
	ROMANIA	20	0.2	22.11	4.12	49.36	1.01	NA
	KUWAIT	17	1.06	20.96	7.73	222.95	2.11	47.88
	ARGENTINA	16	0.08	5.72	0.73	8.3	0.35	54.8
	SERBIA	13	0.36	60.19	5.72	61.92	1.81	NA
	THAILAND	13	0.04	7.21	1.71	2.34	0.43	43.76
	CROATIA	11	0.51	37.35	5.26	48.25	2.32	NA
	LEBANON	10	0.45	47.85	6.5	NA	1.67	NA
	SLOVAKIA	9	0.33	18.94	2.34	9.4	1.43	53.76
	North America	3282	1.82	51.2	14.23	2.25	27.92	70
	Europe	3180	1.56	38.1	9.35	1.82	21.35	59.51
	Asia	580	0.37	21.97	6.06	2.61	7.08	49.56
	South & Central America	400	0.28	12.5	7.68	0.69	23.62	49.95
	Pacific	273	1.83	51	9.63	1.83	28.65	70
	North Africa & Middle East	162	0.76	24.28	5.16	1.14	34.36	46.73
	*Number of publications per million population.

The study received no funding.

Nevertheless, the latest trends could suggest a saturation of scientific production in this field. The next few years will enlighten this point. Interestingly, the interest in this discipline seems to overcome the boundaries of the surgical community as several medical journals publish regularly on this topic. North America, Europe and Australia are historically the leaders in scientific production in bariatric surgery, yet we observed a growing interest in several countries, especially Eastern Asia and the Middle East.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

ETHICAL APPROVAL