Rupesh ; Rajani

Einar Björnsson

Annika Bergquist

Åke Danielsson

Anders Gustavsson

Olof Grip

Per Sangfelt Tor Melin

Sven Wallerstedt

M.D Sven Almer
email: sven.almer@lio.se

a multicenter study

Keywords: Portal hypertension < Hepatology, Epidemiology < Topics, Cirrhosis Venous Thrombosis, Portal Hypertension, Epidemiology, Risk Factors, Cirrhosis, Cancer

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

Portal vein thrombosis (PVT), considered a rare disorder in developed countries [START_REF] Condat | Nonmalignant portal vein thrombosis in adults[END_REF] , is becoming increasingly recognised as a clinical entity. Reliable data on the incidence and prevalence of PVT in the general population or in selected patient groups are lacking. Some attempts have been made using autopsy or inpatient hospital registers from the 1970s and early 1980s [START_REF] Almdal | Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver[END_REF][START_REF] Okuda | Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients[END_REF][START_REF] Ogren | Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies[END_REF] with varied results. In retrospective studies of patients with liver cirrhosis, the prevalence has been reported to lie between 0.6 and 25 with an increased frequency in decompensated disease [START_REF] Okuda | Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients[END_REF][START_REF] Belli | Portal thrombosis in cirrhotics. A retrospective analysis[END_REF][START_REF] Amitrano | Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis[END_REF][START_REF] Tsochatzis | Systematic review: portal vein thrombosis in cirrhosis[END_REF] .

In cases with cirrhosis and hepatocellular cancer the occurrence of PVT has reached 44% [START_REF] Pirisi | Portal vein thrombosis in hepatocellular carcinoma: age and sex distribution in an autopsy study[END_REF] .

The aetiology of PVT is diverse [START_REF] Condat | Nonmalignant portal vein thrombosis in adults[END_REF][START_REF] Webster | Review article: portal vein thrombosis --new insights into aetiology and management[END_REF] , often with multiple concurrent factors implicated [START_REF] Denninger | Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors[END_REF][START_REF] Rosendaal | Venous thrombosis: a multicausal disease[END_REF] .

Local risk factors e.g. liver cirrhosis, hepatobiliary malignancy, abdominal inflammation, infection and surgical intervention are the most common predisposing factors [START_REF] Condat | Nonmalignant portal vein thrombosis in adults[END_REF][START_REF] Webster | Review article: portal vein thrombosis --new insights into aetiology and management[END_REF] . New insights into systemic factors such as inherited or acquired thrombophilia [START_REF] Amitrano | Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis[END_REF][START_REF] Denninger | Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors[END_REF][START_REF] Fisher | Deficiency of natural anticoagulant proteins C, S, and antithrombin in portal vein thrombosis: a secondary phenomenon[END_REF][START_REF] Janssen | Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study[END_REF][START_REF] Primignani | Risk factors for thrombophilia in extrahepatic portal vein obstruction[END_REF][START_REF] Mangia | Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors[END_REF] and primary myeloproliferative disorders (MPD) [START_REF] Primignani | Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis[END_REF][START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF][START_REF] Kiladjian | The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases[END_REF] have improved our understanding of portal vein obstruction especially in non-cirrhotic and patients without neoplasia. The frequencies and distribution of etiologic factors differ in reported case series due to different diagnostic criteria, referral patterns, ethnic groups and geographical regions 4-6, 9, 10, 15, 17, 19 . In the absence of randomised controlled trials the optimal management of PVT is not known although some consensus, based on expert opinion derived from retrospective studies, exists [START_REF] De Franchis | Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension[END_REF][START_REF] Chawla | Review article: the modern management of portal vein thrombosis[END_REF][START_REF] Deleve | Vascular disorders of the liver[END_REF] .

The aim of this study was to investigate the epidemiology, clinical presentation and survival in an unselected cohort of adult patients with PVT in Sweden. The date of diagnosis was defined as the year and month on which the obstruction was evident on at least one of the following imaging modalities: ultrasonography (performed in 156 patients), computerised tomography (n=129), angiography (n=20) or magnetic resonance imaging (n=16). The thrombosis was classified as acute if a recent intraluminal obstruction was visualised, and chronic if a portal cavernoma, i.e. portoportal collaterals were present [START_REF] Condat | Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy[END_REF] .

PATIENTS AND METHODS

Patients

Information on clinical characteristics, catchment area, investigations undertaken, laboratory findings, treatment, as well as the outcome was extracted from the medical records using structured case record forms. The presence of cirrhosis or not was based on clinical data, i.e. past history of liver disease, results of imaging and laboratory studies and by liver biopsy or, in the case of loss to follow-up, the last visit. Causes of death were acquired from the medical records, or if absent, from the Cause-of-death register, the National board of health and welfare, Stockholm. Register search was made possible through the national registration number, unique for each citizen [START_REF] Lunde | The personnumber systems of Sweden, Norway, Denmark, and Israel[END_REF] .

Epidemiology

Patient care during the study period was almost solely public and population based, and the referral patterns based on geographic grounds. To assure full catchment of PVT cases, analysis of epidemiology was restricted to primary catchment area-patients in six centres which had used both in-and outpatient registers to identify patients. The mean population figure for each year and each primary catchment area were available from 1995 and onwards from Statistics Sweden, Stockholm. The combined population of these six centres was 1.

Statistics

Comparisons between independent groups were made by Mann-Whitney U-test and Kruskal-Wallis one-way analysis of variance as appropriate for continuous variables. For categorical variables chi-squared tests were performed and Fisher´s exact test used when more than 20% of the expected values were less than five. The Kaplan-Meier estimate was applied for calculating overall and transplantation-free survival rates. Univariate analysis of factors at

Ethics

The study was approved by the committee of human ethics at all participating centres.

RESULTS

173 patients (93 men) with a median of 17 cases per hospital (range 1-33) were identified and grouped into three strata; N-PVT, non-malignant, non-cirrhotic PVT (n=89), C-PVT, nonmalignant, cirrhotic PVT (n=38), and, M-PVT, malignant PVT (n=46). Fifty-five patients (32%) were diagnosed at the two transplantation centres. The median age at diagnosis was 57 years (range 15-94). One patient (0.6%) was lost to follow-up due to migration when the study ended in October 2004. Epidemiology 124 new cases of PVT were diagnosed at the six centres eligible for analysis of epidemiological data, of whom 97 patients (56% of all patients) were from the primary catchment areas. The mean age-standardised incidence and prevalence rates of PVT were calculated to be 0.7 (95% CI 0.3-1.2) per 100,000 inhabitants per year and 3.7 (95% CI 2.6-4.8) per 100,000 inhabitants, respectively. The percentage of patients living in the primary catchment area of liver transplantation and non-liver transplantation centres were comparable, 81% and 78%, respectively (NS).

Risk factors

The spectrum of risk factors is listed in Table 1. The most prevalent risk factor was a liver disorder, present in 70 patients (40%) of whom 54 (76%) had liver cirrhosis. Alcoholic liver disease was present in 21 patients (12%), viral hepatitis in 15 (9%), cryptogenic cirrhosis in 14 (8%), autoimmune hepatitis in 6 (3%), NAFLD in 4 (2%) and other liver disorders in 10 (6%).

Of systemic factors, thrombophilic conditions were present in 22% of patients and 19% of all patients had a previous history of any extra-splanchnic thrombotic event with a trend to concurrent presence of these two (chi-square 3.3; df 1, p=0.07). Eighteen patients (11%) had an underlying MPD. The occurrence of trombophilia and MPD was 26% and 18% in N-PVT, 17% and 6% in C-PVT and, 18% and 2% in M-PVT patients, respectively. MPD and severe infections were more common in N-PVT compared to the two other groups (p=0.015 and p=0.046, respectively).

Overall, 76 patients (44%) had one or more local precipitating factors, 42 patients (24%) had a systemic risk factor, and 38 (22%) had a combination of both. Considering the presence of any risk factor 76 patients (44%) had one risk factor identified; two or more risk factors were present in 80 patients (46%). No obvious risk factor was evident in 17 patients (10%).

Clinical characteristics

N-PVT patients were younger at the time of diagnosis (median age 54 years) compared to patients with C-PVT (60 years) or M-PVT (67 years), p<0.001 (for both comparisons) and presented more often with fever, 48% (p=0.004). On the other hand were ascites (p<0.001), splenomegaly (p<0.001), oesophageal varices (p=0.001), jaundice (p=0.005) and signs of hypertensive gastropathy (p=0.017) more prevalent in C-PVT and M-PVT. Abdominal pain was a common complaint in N-PVT (78%) and M-PVT patients (70%), but less frequent in C-PVT (46%) (p=0.002). Ileus was diagnosed in 6 cases (4%). Eight patients (5%) were asymptomatic of whom six were N-PVT patients.

Classification according to Child-Pugh was, for the cirrhotic patients (n=38) grade A 14%, grade B 61% and grade C 25%, and, for patients with malignancy (n=46), 0%, 87% and 13%, respectively.

The median C-reactive protein (CRP) in N-PVT (67mg/L) and M-PVT (44mg/L) was higher than in C-PVT patients (13mg/L) (p=0.003). Few patients had an increase in prothrombin INR and the transaminase levels were generally normal or slightly elevated.

Diagnosis

An acute thrombosis was present in 128 patients (74 %), chronic thrombosis in 32 (18%) and was unspecified in 13 (8%). The thrombosis was limited to the portal vein in 102 patients (59%) and in the remaining 71 patients (41%) one or more accessory veins, i.e. the mesenteric and/or splenic veins were also involved. PVT engaging accessory veins, were found in 49% N-PVT, 29% C-PVT and 35% M-PVT patients (NS). thrombosis and in seven the nature of the thrombosis was not specified. The median duration of treatment was 6.4 (range 0.1-114) months and the mean duration was 16 months.

Medical treatment and interventions

Details of interventions performed at diagnosis and during follow-up are given in

Anticoagulant therapy was more common in N-PVT patients (85%) than those with C-PVT (70%) or M-PVT (50%), (p=0.004) while diuretics were less frequent in N-PVT patients (p<0.001). All six patients (4%) given thrombolysis (one local and five systemically) were non-malignant non-cirrhotic; five of these cases had an acute PVT and three of them had a thrombosis involving accessory veins as well. Three patients (2%) underwent TIPS at diagnosis, all of which had an underlying liver disease. In two patients (both N-PVT) surgical shunting procedures were performed during the first year (portosystemic shunt n=1) or the third year (splenorenal shunt n=1) after diagnosis due to GI-bleeding and varices. Eight patients (5%) underwent liver transplantation (secondary to an underlying hepatic disorder), of whom one ultimately died, six days after transplantation. Not more than six patients (3%) underwent bowel resection due to ischemia.

Information on recanalisation was available in 61 patients (35%). Partial or complete recanalisation was seen in 70% during the first year of follow-up and 72% at the last followup visit. 36 of 44 patients (82%) with recanalisation had received anticoagulation. An increased obstruction in the portal venous tract was observed in 7% and remained unchanged in 21%. Recanalisation frequencies did not differ between N-PVT, C-PVT and M-PVT patients (data not shown).

Survival

The median follow-up was 2.5 years (range 0-9.7). A total of 74 patients (43%) died during the follow-up period. Causes of death are listed in Table 3. Two patients that had not received The overall survival at 1 and 5 years was 69% (95% CI 61-76) and 54% (95% CI 46-62), respectively (Figure 1). In N-PVT (n=89) the survival at 1 and 5 years was 92% (95% CI 86-98) and 76% (95% CI 66-86), respectively. For C-PVT (n=38) the survival at 1 and 5 years was 53% (95% CI 37-69) and 38% (95% CI 19-58), respectively and those with M-PVT, n=46) the 1 and 5 year survival was 37% (95% CI 23-51) and 24% (95% CI 11-37), respectively.

Factors at diagnosis that influenced the transplantation-free survival were assessed by using univariate analysis. The use of anticoagulants at diagnosis or during the first follow-up year was not significantly related to survival (p=0.31 and p=0.11, respectively). Age, ascites, encephalopathy, albumin, bilirubin, prothromin time, cirrhosis, malignancy and ALP had an impact on survival (p<0.001) as also ALT (p=0.002), platelet count (p=0.003), presence of oesophageal varices (p=0.005) and splenomegaly (p=0.007). The presence of a thrombotic extension into the mesenteric vein did not significantly influence the survival.

The results of a multivariate analysis for the total cohort and for patients with non-malignant PVT (n=127) are presented in Table 4, showing that age, bilirubin, cirrhosis and malignancy independently influenced survival (p<0.001). Male sex had an independent prognostic value for decreased survival in the total cohort (p=0.029) but not for patients with non-malignant PVT.

DISCUSSION

We report the epidemiology, risk factors and outcomes of a large group of unselected patients with PVT. The study is the first in which both incidence and prevalence rates of PVT are reported in a population-based cohort. We used in-and outpatient registers and calculated the mean age-standardised incidence and prevalence rates to be 0.7 per 100,000 inhabitants per year and 3.7 per 100,000 inhabitants, respectively. The inpatient register contains individualbased information on a nationwide level since 1987 and a discharge diagnosis is available in 99% of all hospitalised patients [START_REF]Epidemiologiskt Centrum, Patientregistret 1964-2005 Kvalitet och innehåll[END_REF] . The diagnosis of PVT has not been validated but results on other disorders have shown a 85-90% accuracy [START_REF]Epidemiologiskt Centrum, Patientregistret 1964-2005 Kvalitet och innehåll[END_REF] .

Nationwide register data limited to in-patients for the years 1981-85 in Denmark gave an estimated incidence rate of 0.27 per 100,000 inhabitants and year 2 , i.e. half the rate reported herein. In contrast to that study, we also included data from out-patient registers and covered a later time period, 1995-2004, during which the diagnostic awareness of this condition has increased and better imaging modalities have become available.

Population-based prevalence rates for PVT have been addressed in two older autopsy studies.

In the Japan Autopsy Register of 1975-1982 (n=247,728) PVT was found in 0.05% (≈ 50 per 100,000) (adapted from Okuda et al in [START_REF] Okuda | Incidence of portal vein thrombosis in liver cirrhosis. An angiographic study in 708 patients[END_REF] ), whereas in Malmö city, Sweden, the prevalence was as high as 1.0% (≈ 1000 per 100,000) in 1970-1982 (n=23,796 representing 84% of all inhospital deaths) [START_REF] Ogren | Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies[END_REF] . The difference between these results are striking and could be due to a lower occurrence of PVT in Japan compared to Europe. However, considering that both studies originate from necropsy results, in which there is a selection for the more severe cases per se, variable autopsy rates in different centres as well as ascertainment bias [START_REF] Ogren | Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies[END_REF] , our lower prevalence rate should be considered more reliable. This assumption is underlined by the high proportion of patients with intra-abdominal neoplasia (67%) in one of the autopsy studies [START_REF] Ogren | Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies[END_REF] as compared to in our study (21%) and in a previous large case series (24%) [START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF] . Although a thorough search of the in-and outpatient registers was performed it cannot be excluded that we might have missed some patients with advanced malignancy as well as asymptomatic cases with underlying cirrhosis. At the time of our study screening for hepatocellular carcinoma was not routinely performed in the participating centres. Thus, the incidence and prevalence rates of PVT here are possibly underestimated.

New insights in the aetiology of PVT have revealed the presence of more than one risk factor in a high proportion of patients [START_REF] Denninger | Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors[END_REF][START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF][START_REF] Amitrano | Prognostic factors in noncirrhotic patients with splanchnic vein thromboses[END_REF] . This was confirmed in our study with 23% having a combination of a local and a systemic risk factor compared to 16% in a study from the Netherlands [START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF] . Moreover, and despite that not all patients had undergone a full diagnostic work-up for thrombophilic disorders and MPD, almost half of the patients (46%) had two or more risk factors (regardless of if local or systemic). In an Italian single center study of noncirrhotic non-malignant patients with thrombosis confined to the splanchnic veins, the occurrence of two or more risk factors was 27% [START_REF] Amitrano | Prognostic factors in noncirrhotic patients with splanchnic vein thromboses[END_REF] compared to 37% in our N-PVT patients.

Cultures of progenitors [START_REF] Valla | Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders[END_REF] were not performed and the JAK2-V617F mutation analysis [START_REF] Primignani | Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis[END_REF] was not available at the time of study closure. We have recently observed the presence of the JAK2-mutation in 19% of PVT patients without malignancy or cirrhosis (unpublished observation). These findings suggest that a thorough diagnostic work-up in order to optimise the management of patients is warranted irrespective of the presence of a local precipitating factor.

Local factors were more common in men (p=0.005) than in women in whom systemic factors (e.g. rheumatoid disorders) dominated (p=0.019), which has not previously been reported. This observation is probably due to that liver cirrhosis and hepatocellular carcinoma are more common in men.

The prevalence of inherited or acquired thrombophilia was 22%. Although the highest frequency was seen in N-PVT patients (26%), there was no statistically significant difference compared to C-PVT (17%) and M-PVT (18%) patients. The presence of trombophilia and MPD at diagnosis did not significantly effect survival in our univariate analysis (p=0.86 and p=0.36, respectively).

Due to the lack of randomised controlled trials the best treatment for PVT is mainly empirical 7, 20-22 .

Partly based on retrospective studies from France, in which 90% achieved partial or complete recanalisation [START_REF] Condat | Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy[END_REF] without an increased risk of bleeding [START_REF] Condat | Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy[END_REF] , anticoagulant therapy has been advocated for patients with acute non-malignant and non-cirrhotic PVT [START_REF] De Franchis | Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension[END_REF][START_REF] Chawla | Review article: the modern management of portal vein thrombosis[END_REF][START_REF] Deleve | Vascular disorders of the liver[END_REF] . Recanalisation was however achieved only in 66% (31% partial and 34% complete) of our N-PVT patients during the first year after diagnosis, with a minor increase to 68% when analysing the total follow-up period. Although, these results must be interpreted with caution as data on recanalisation was limited, they are in line with a recently published retrospective Italian series in which 45% of N-PVT patients achieved complete recanalisation. However, findings in a prospective study have furthermore indicated a limited recanalisation rate of 44% 28 . Our overall survival rates at 1 and 5 years were consistent with the findings in a similar multicentre series from the Netherlands 17 , being 69% vs. 70%, and, 54% vs. 61%, respectively. A slightly lower survival in our study could be attributed to a higher frequency of concomitant mesenteric vein thrombosis (31% vs. 11%), which has been associated with decreased survival [START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF][START_REF] Orr | Chronic mesenteric venous thrombosis: evaluation and determinants of survival during longterm follow-up[END_REF][START_REF] Kumar | Mesenteric venous thrombosis[END_REF] , although this was not evident in our univariate analysis.

The survival rates for N-PVT patients were good and similar to findings in previous series [START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF][START_REF] Amitrano | Prognostic factors in noncirrhotic patients with splanchnic vein thromboses[END_REF] . However, the 5-year survival for such patients was higher in an Italian cohort being 93% [START_REF] Amitrano | Prognostic factors in noncirrhotic patients with splanchnic vein thromboses[END_REF] compared to 76% in our study. A more favourable outcome could be explained by their single tertiary referral centre holding a liver transplantation unit, and by a uniform management strategy in younger patients (median age at diagnosis was 45 compared to 54 year in our study). Reports comparing the survival in cirrhotic patients with and without PVT are lacking in the literature. The median one-year cumulative survival for C-PVT was 53% in our study, i.e. worse than the 78% reported for cirrhotic patients in general [START_REF] D'amico | Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies[END_REF] .

Although the use of anticoagulants during the first year after diagnosis was high (65%) (compared to 34% in the Italian and 25% in the Dutch study), we did not observe an increased survival with anticoagulation, nor has this been evident in other studies except for one study on chronic portomesenteric thrombosis patients (n=60) [START_REF] Orr | Chronic mesenteric venous thrombosis: evaluation and determinants of survival during longterm follow-up[END_REF] . In that report, mortality was secondary to portal hypertension, in contrast to our study in which the cause of death primarily was related to the underlying condition [START_REF] Janssen | Extrahepatic portal vein thrombosis: aetiology and determinants of survival[END_REF] . We had two deaths due to variceal bleeding in patients who had not been anticoagulated. Bowel resection was performed in six patients (3%); death due to intestinal ischemia was very rare and occurred in only one (0.6%) patient.

There are some limitations and strengths to our study. It is a retrospective analysis of a heterogeneous, although large patient cohort, and, a standardized diagnostic work-up had not been applied. To exclude an undue selection and referral bias as much as possible, we included all PVT patients treated at both academic and non-academic hospitals. It is possible that some patients with thrombophilia or MPD went undetected. To assure full catchment of all PVT cases, analysis of epidemiology was restricted to primary catchment area-patients in the six centres which had used both in-and outpatient registers to identify patients. Treatment bias is possibly reduced by a more recent study period during which dramatic changes in therapeutic options have evolved.

In conclusion, the mean age-standardised incidence and prevalence rates of PVT in Sweden were calculated to be 0.7 per 100,000 inhabitants per year and 3.7 per 100,000 inhabitants, respectively. A liver disorder is a frequent risk factor and the presence of concurrent prothrombotic factors is common. The prognosis is variable and highly dependent on underlying disease. The survival rate is high in the absence of cirrhosis and/or malignancy.

STATEMENT OF INTERESTS

This study was supported by unrestricted grants from Futurum -the academy of health care;

  was performed in collaboration with the Swedish Internal Medicine Liver Club, a nation-wide network of university hepatologists. We searched the computerised diagnosis databases of eleven hospitals, comprising all nine university hospitals, including the liver transplantation centres in Sweden. The background population of these centres was 4.4 million, which constitutes approximately half of the Swedish population. Consecutive patients between January 1995 and October 2004 registered with the ICD-9 (452 and 572B) or ICD-10 (I81, and K75.1) diagnosis codes suggestive of PVT were identified. All patients with partial or complete thrombotic obstruction of the portal vein visualised at imaging, were included.

  when performed. Child-Pugh scores were assessed in cirrhotic patients. The presence of any liver disease, intra-abdominal malignancy, gastrointestinal inflammation, abdominal infection or abdominal surgery performed less than three months prior to diagnosis, were categorised as local risk factors. Thrombophilias, blood disorders, any previous thrombosis, extra-abdominal malignancy, hormone therapy, systemic infection, rheumatoid disorders and pregnancy were considered systemic aetiological factors.

5 Follow

 5 -up was from the date of diagnosis until either death or study closure in October 2004,

3 million,

 3 comprising approximately 15% of the Swedish population in 2001. The mean incidence rate was calculated for the years 1995-2003 and the mean prevalence rate for the years 2001-2003. Crude rates were age-standardised according to the population census in 1970. Patients were not included in the analysis of prevalence rates following orthotopic liver transplantation.

  was assessed using the log-rank test. Multivariate analysis was carried out using Cox´s proportional hazard model. Results were expressed as medians and range. All analyses were carried out in SPSS for Windows version 16.0 (SPSS Inc, Chicago, IL). Two-tailed p values < 0.05 were considered statistically significant.

  variceal bleeding. There was one fatality (0.6%) due to intestinal ischemia.

Figure 1 .

 1 Figure 1. Overall survival rates for all patients with portal vein thrombosis, for patients with

Table 2 .

 2 Atdiagnosis 113 patients (65%) were administered anticoagulant therapy with additionally three patients during follow-up. Treatment was usually started with LMWH and followed by oral anticoagulation. Of the 116 anticoagulated patients, 94 had an acute thrombosis, 15 chronic

	F o r
	P
	e
	e r
	R
	e
	v i e
	w

Table 1a .

 1a Local risk factors in Portal vein thrombosis (n=173). Patients can have more than one factor.

			N %
	Liver disease		70 40
	With cirrhosis		54
	Without cirrhosis		16
	Intra-abdominal malignancy		37 21
	Hepatocellular cancer		21
	Colorectal cancer		4
	F o r F o r F o r GI-inflammation (n=166)* Other Abdominal surgery# Severe local infection (n=169)* F o r	12 24 14 8 5 5 3
	No local factor identified	P P P P	59 34
	e e r e e r e e r e 'One patient had alcoholic liver disease and viral hepatitis. *Denotes number of evaluable cases. #Within three months prior to diagnosis. e r
			R R R R
	e e e e The Medical Research council of Southeast Sweden (no: FORSS-5784); and The Swedish Society of Medicine (Bengt Ihre fonden). Preliminary data has been presented in abstract v i e v i e v i e v i e form in Scand J Gastroenterol 2006;41(suppl. 242):32 and in Gut 2006; 55 (Suppl V) A35. w w w w
			18 19

Table 1b .

 1b Systemic risk factors in Portal vein thrombosis (n=173). Patients can have more than one factor.

				N %
	Thrombophilic factor † (n=126)*			28 22
	Factor V Leiden mutation			13
	Hyperfibrinogenemia			4
	Lupus anticoagulant			4
	Cardiolipin antibodies			3
	Antithrombin deficiency ‡			3
	Prothombin gene mutation			2
	Protein S deficiency ‡ Previous thrombosis (n=156)* Venous F o r		1 29 19 19
	Arterial Myeloproliferative disorder (n=158)* P		10 18 11
	Polycytemia vera rubra	e		12
	Essential Thrombocythemia Chronic Myeloid Leukaemia	e r	5 1
	Severe systemic infection (n=169)* Hormone replacement therapy (n=75/80)*	14 8 9 12 R
	Rheumatoid disorder (n=165)* Blood malignancy Lymphoma Leukaemia		8 5 e 6 13 4 2 v i e
	Extra-abdominal malignancy Oral contraceptives (n=74/80)*			3 7 3 4	w
	Pregnancy (n=79/80)*			3 4
	No systemic factor identified			93 54
	†Two patients had more than one factor (antithrombin deficiency and hyperfibrinogenemia, protein S
	deficiency and lupus anticoagulant, respectively).
	*Denotes number of evaluable cases.
	‡Deficiency due to liver failure not included i.e. patients with combined low levels of protein S and
	protein C and/or antithrombin were excluded.
				20

Table 2 .

 2 Interventions in 173 patients with portal vein thrombosis.

				During follow-
		At diagnosis	up
		n	%	n	%
	Anticoagulants	113	65	116	67
	Heparin/LMWH	102		103
	Coumarin derivatives	63		70
	Thrombolysis	6	3	6	3
	Acetylsalicylic acid	11	6	14	8
	Other antiplatelet drugs	2	1	2	1
	Diuretics	64	37	71	41
	Betablockers	64	37	72	42
	Isosorbide mononitrate	11	6	13	8
	Band ligation	26	15	36	21
	Sclerotherapy	20	12	23	13
	TIPS or surgical shunting	3	2	5	3
	Liver transplantation*	1	1	8	5
	Splenectomy	0	0	5	3
	Bowel resection	4	2	6	3
	*Due to underlying liver disease
	FU, Follow-up; LMWH, low-molecular-weight heparin; TIPS, transjugular intrahepatic
	portosystemic shunting.

Table 3 .

 3 Cause of death in patients with portal vein thrombosis (n=74).

		PVT (n=74)
		n	%
	Malignancy	31	42
	Intra-abdominal*	28
	Other	3
	Liver failure	16	22
	Cardiac failure	9	12
	Multiorgan failure	6	8
	Infection	4	5
	Variceal bleeding	2	3
	Intestinal ischemia	1	1
	Other, non-liver related	5	7
	* Hepatocellular cancer (n=18), liver metastasis (n=4), biliary (n=2), colorectal (n=2),
	pancreatic (n=1) and gastric cancer (n=1).

Table 4 .

 4 Multivariate survival analysis of characteristics at diagnosis in 173 patients with portal veinthrombosis. Relative risk (RR) of death is given for the total cohort and separately for those with non-malignant portal vein thrombosis (n=127).

			PVT (n=173)			Non-malignant PVT (n=127)
		RR		95% CI		p	RR		95% CI		p
	Age
	<=50	1.0					1.0
	51-60	1.9	0.8	-	4.3	0.14	2.9	1.0	-	8.4	0.06
	> 60	4.2	2.0	-	8.6	<0.001	12.0	4.1	-	34.9	<0.001
	Sex
	Female	1.0					1.0
	Male	1.9	1.1	-	3.5	0.03	1.1	0.6	-	2.3	0.72
	Bilirubin (µmol/L)
	<= 20	1.0					1.0
	> 20	4.8	2.6	-	8.8	<0.001	3.8	1.7	-	8.6	0.00
	Albumin (g/L)
	<= 30	1.0			31	7.90 -1.0			31	7.90
	> 30	0.9	0.5	-	1.5	0.58	1.2	0.5	-	2.8	0.62
	Mesenteric vein thrombosis
	Absent	1.0					1.0
	Present	1.2	0.7	-	2.2	0.55	0.8	0.4	-	1.8	0.61
	Cirrhosis
	Absent	1.0					1.0
	Present	2.7	1.6	-	4.7	<0.001	7.3	2.9	-	18.3	<0.001
	Abdominal inflammation
	Absent	1.0					1.0
	Present	0.5	0.2	-	1.2	0.11	1.1	0.3	-	3.7	0.88
	Malignancy
	Absent	1.0
	Present	3.5	1.9	-	6.6	<0.001

Alimentary Pharmacology & Therapeutic


Martijn Huisman
email: ma.huisman@vumc.nl

Ricardo Araya

Debbie A Lawlor

Johan Ormel

Frank C Verhulst

Albertine J Oldehinkel

Cognitive ability, parental socioeconomic position and internalising and externalising problems in adolescence: Findings from two European cohort studies

Keywords: adolescence, socioeconomic factors, mental health, ALSPAC, TRAILS, cognitive ability CA=cognitive ability; SEP=socioeconomic position

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Two important predictors of internalising and externalising problems in adolescents are parental socioeconomic position (SEP) [START_REF] Olak | Socioeconomic position and mental health problems in pre-and early-adolescents: the TRAILS study[END_REF][START_REF] Ashford | Early risk indicators of internalizing problems in late childhood: a 9-year longitudinal study[END_REF][START_REF] Sund | Psychosocial correlates of depressive symptoms among 12-14-year-old Norwegian adolescents[END_REF][START_REF] Kaltiala-Heino | Adolescent depression: the role of discontinuities in life course and social support[END_REF][START_REF] Goodman | The role of socio-economic status gradients in explaining differences in US adolescent health[END_REF][START_REF] Mcloyd | Socioeconomic disadvantage and child development[END_REF][START_REF] Mccleod | Trajectories of poverty and children"s mental health[END_REF] and cognitive deficits [START_REF] Einfeld | Tonge BJ Psychopathology in young people with intellectual disability[END_REF][START_REF] Chadwick | Psychiatric diagnoses and behaviour problems from childhood to early adolescence in young people with severe intellectual disabilities[END_REF][START_REF] Koskentausta | CBCL in the assessment of psychopathology in Finnish children with intellectual disability[END_REF][START_REF] Emerson | Prevalence of psychiatric disorders in children and adolescents with and without intellectual disability[END_REF][START_REF] Dekker | Emotional and behavioural problems in children and adolescents with and without intellectual disability[END_REF][START_REF] Dekker | DSM-IV disorders in children with borderline to moderate intellectual disability, II: child and family predictors[END_REF] or abilities (CA) in the adolescent [START_REF] Fergusson | Show me the child at seven II: childhood intelligence and later outcomes in adolescence and young adulthood[END_REF]. Previous studies provided substantial evidence that children and adolescents from lower socioeconomic groups more often manifest internalising and externalising problems, although the precise relation between SEP and specific types of problems remains unclear [START_REF] Bradley | Socioeconomic status and child development[END_REF]. Among adolescents, lower parental SEP is related to most of the common mental health problems, including internalising problems [START_REF] Ashford | Early risk indicators of internalizing problems in late childhood: a 9-year longitudinal study[END_REF], depression [START_REF] Sund | Psychosocial correlates of depressive symptoms among 12-14-year-old Norwegian adolescents[END_REF][START_REF] Kaltiala-Heino | Adolescent depression: the role of discontinuities in life course and social support[END_REF][START_REF] Goodman | The role of socio-economic status gradients in explaining differences in US adolescent health[END_REF][7] and delinquent and rule-breaking behaviour [START_REF] Olak | Socioeconomic position and mental health problems in pre-and early-adolescents: the TRAILS study[END_REF][6] [START_REF] Mccleod | Trajectories of poverty and children"s mental health[END_REF].

Low parental SEP is believed to be an important risk factor for offspring mental health problems because it reflects exposure to a disadvantageous social environment during important developmental phases early in the life course. Such disadvantaged environments may be characterised by economic hardship, heightened levels of stress, poor parenting, and child abuse within the family, or by neighbourhood factors such as poor housing, substance abuse and delinquency. Associations of these factors with internalising or externalising problems in children and adolescents have been demonstrated [START_REF] Mcloyd | Socioeconomic disadvantage and child development[END_REF][START_REF] Mccleod | Trajectories of poverty and children"s mental health[END_REF] [ [START_REF] Bradley | Socioeconomic status and child development[END_REF][START_REF] Bolger | Psychosocial adjustment among children experiencing persistent and intermittent family economic hardship[END_REF][START_REF] Caspi | Neighborhood deprivation affects children"s mental health: environmental risks identified in a genetic design[END_REF][START_REF] Feinberg | Parenting and adolescent antisocial behaviour and depression: evidence of genotype x parenting environment interaction[END_REF][START_REF] Reijneveld | Area deprivation and child psychosocial problems: a national cross-sectional study among school-aged children[END_REF][START_REF] Schneiders | Neighborhood socioeconomic disadvantage and behavioral problems from late childhood into early adolescence[END_REF][START_REF] Zwaanswijk | Help seeking for emotional and behavioral problems in children and adolescents: a review of recent literature[END_REF].

To improve our understanding of the aetiology of internalising and externalising problems it is necessary to understand better how the two predictors -SEP and CAmight work together. In the current study we investigated the possibility that CA is a moderator of the association between parental SEP and internalising and externalising problems in adolescents.

Our hypothesis that CA would modify the association of SEP with adolescent behaviour was based on the following reasoning. Higher CA has been shown to be associated with resilience to adverse circumstances in children and adolescents [START_REF] Masten | The development of competence in favorable and unfavorable environments[END_REF].

Children with a relatively higher CA appear to find it easier to regain functioning -to "rebound or recoil" -in the face of adversity than children with lower CA [START_REF] Garmezy | Children in poverty: resilience despite risk[END_REF]. Given the definition of CA, or intelligence ("[…] a very general mental capability that, among other things, involves the ability to reason, plan, solve problems, think abstractly, comprehend complex ideas, learn quickly and learn from experience." [START_REF] Gottfredson | Mainstream science on intelligence: an editorial with 53 signatories, history, and bibliography[END_REF]), the greater resilience to adverse circumstances of children and adolescents with greater CA might be because these individuals are more successful in finding solutions for stressful situations or learn more quickly how to avoid them. If this is true, then it would be expected that, given similar circumstances of growing up in highly stressful environments (low SEP), adolescents with higher CA would have reduced odds of adverse outcomes compared to their lower CA peers. In other words, a high level of CA might buffer against the odds of internalising and externalising problems associated with growing up in a family with low SEP. This hypothesis is in line with previous findings demonstrating that CA is associated with resilience and corresponds with stress-resilience models [START_REF] Masten | The development of competence in favorable and unfavorable environments[END_REF][23] [START_REF] Luthar | Vulnerability and resilience: a study of high-risk adolescents[END_REF][START_REF] Masten | Competence in the context of adversity: pathways to resilience and maladaptation from childhood to late adolescence[END_REF][START_REF] Buckner | Characteristics of resilient youths living in poverty: the role of self-regulatory processes[END_REF].

Resilience models in early life developmental research involve moderating relations with stress or specific stressors. Children who are faced with life stresses but develop into well functioning adolescents and adults regardless are labelled "resilient" [START_REF] Luthar | Vulnerability and resilience: a study of high-risk adolescents[END_REF].

To our knowledge our specific hypothesisthat the increased odds of internalising and externalising behaviour in adolescents from families with lower SEP will be less apparent for adolescents with greater CA -has not been previously tested. We therefore sought to examine this hypothesis using data from two longitudinal cohort studies; one from the UKthe Avon Longitudinal Study of Parents and Children (ALSPAC)and one from the Netherlandsthe TRacking Adolescents" Individual Lives Survey (TRAILS). We chose to investigate the hypothesis in these two wellestablished cohort studies because evidence for or against the hypothesis would be strengthened if it were possible to replicate it in more than one relevant study.

Consistency of findings between these cohorts will strengthen the basis for generalising them to adolescents in western societies in general.

Data and Methods

Participants

Avon Longitudinal Study of Parents and Children (ALSPAC)

The target population consisted of pregnant women and their partners who were residing in Avon at the time of pregnancy, and who had an expected delivery date between 1 st of April 1991 and 31 st December 1992. The study started during the early phases of pregnancy of these women, and is ongoing. A total of 14,541 pregnant women were enrolled in the study and of these there were 13,971 live-born infants who survived to at least 1 year of age (48 % female). A detailed description of the methodology of the study is provided elsewhere [START_REF] Golding | ALSPAC -The Avon Longitudinal Study of Parents and Children. I. Study methodology[END_REF]. Ethical approval for the study was obtained from the ALSPAC Law and Ethics Committee and the Local Research Ethics Committees.

When the children were 8 years old they were invited to a clinic for psychometric and psychological testing. A total of 7,171 (~60% of those invited) attended the clinic. At age 13 the main caretaker of the child (in most cases the mother) was asked to fill out a questionnaire that included questions on behaviour. A total of 6,852 questionnaires were returned and 4,041 participants had complete data on all of the characteristics used in this study (50 % female).

Tracking Adolescent's Individual Lives Survey (TRAILS)

The TRAILS target population included all 10-to 11-year-old children living in three large cities and some rural areas in the North of the Netherlands. The present study involved data from baseline (T1; data collection March 2001-July 2002) and first follow-up (T2; September 2003-December 2004). At baseline, 76% of eligible households were enrolled in the study (N=2,230). The mean age of the participants at baseline was 11.09 (SD=0.56) years, and 50.8% of the participants were girls. Of the 2,230 baseline participants, 96.4% participated at T2 (N=2,149). The mean age of participants at T2 was 13.55 (SD=0.53), and at T2 51.2% of the participants were girls. Further information on the sampling procedure, methods and aims of the study is given elsewhere [START_REF] Huisman | Cohort profile: The Dutch "TRacking Adolescents" Individual Lives" Survey; TRAILS[END_REF] [START_REF] Winter | Evaluation of non-respons bias in mental health determinants and outcomes in a large sample of Dutch pre-adolescents[END_REF].

The choice of dependent and independent variables and the timing of measurement were selected so that comparability between the studies was maximal.

Independent variables

Parental SEP was measured with mother"s highest educational attainment and with household income. Other indicators of SEP were available in both studies, including occupational position of the mother and education and occupation of the father. However, we limited our analyses to mother"s education and household income because these two indicators were the most comparable between the two studies and were considered to be important determinants of parent-child interaction within families.

Mother"s educational attainment was obtained only at baseline in both studies (i.e. at 32 weeks gestation in ALSPAC and at age 10-11 years in TRAILS). This difference in timing of collecting data on maternal education his is unlikely to compromise comparability between the two studies because education attainment changes little after early adulthood. The timing of measurement of household income used in our analyses also varied (age 4 years in ALSPAC and age 10-11 years in Trails). In absolute terms household income is likely to increase as children become older but over the 6 years difference in age we would anticipate that the relative positions of households would be similar.

CA was measured with the Wechsler Intelligence Scale for Children (WISC-III) in ALSPAC [START_REF] Wechsler | WISC-III UK Wechsler Intelligence Scale for Children -Third edition UK Manual[END_REF], when the children were 8 years old. In TRAILS, two subtests (the vocabulary and block design subsets) of the revised Wechsler Intelligence Scale for Children (WISC-R) were administered at baseline when children were around 10-11 years old [START_REF] Wechsler | Wechsler Intelligence Scale for Children-Revised[END_REF]. Total IQ scores derived from these tests were included in analyses as measures of CA. The total IQ in TRAILS was estimated from the two subtests with the method proposed by Sattler [START_REF] Sattler | Assessment of children[END_REF].

Mother"s history of depression was measured with the Edinburgh Post-natal Depression Score [START_REF] Cox | Development of the Edinburgh Postnatal Depression Scale[END_REF] at two time points during pregnancy in ALSPAC. We used the mean of these two scores and divided this into tertiles to categorise the degree of mother"s exposure to depressive problems. In TRAILS mother"s history of depressive problems was assessed at baseline, during an interview. The interviewer presented the respondents with a description of the symptoms of depression and asked if the respondent had ever suffered from these symptoms, and had received treatment or medication for these symptoms. Respondents were categorised into three mutually exclusive categories: 1) did not suffer from depressive problems; 2) ever suffered from depressive problems but never received treatment; and 3) ever suffered from depressive problems and had at least once received treatment.

Dependent variables

The term internalising disorders refers to the conditions whose central feature is disordered mood or emotion. Conditions designated as externalising disorders are ones whose central feature is deregulated behaviour [35]. Because the aetiology and development of internalising and externalising problems during adolescence differs we investigated relationships of parental SEP and CA with each problem separately.

In ALSPAC, the main measure of internalising and externalising problems during adolescence was the parent-reported Strengths and Difficulties Questionnaire (SDQ) [START_REF] Goodman | The Strengths and Difficulties Questionnaire: A Research Note[END_REF], which includes information on hyperactivity, conduct problems, emotional problems and peer problems. We selected the conduct problems scale and the emotional problems scale as measures of externalising and internalising problems respectively. Scale scores were derived by computing the mean score on the items of the scale (Appendix Table 1). The SDQ was administered when the children were aged 13 years.

In TRAILS information on internalising and externalising problems came from the Childhood Behavior Checklist (CBCL) [START_REF] Achenbach | Manual for the child behaviour checklist/4-18 and 1991 profile[END_REF]. We used the internalising and externalising problem scales as outcome. Scale scores were derived by computing the mean score on the items of the scale (Appendix Table 1). These outcomes in TRAILS were taken from the first follow-up (T2), which was administered when the mean age of children was 13.6 years. Although the number of items included in the SDQ and CBCL scales differs and CBCL can be considered to provide more detailed information, validation research has demonstrated that the SDQ conduct scale and emotional scale detect internalising and externalising problems, respectively, as well as the CBCL scales [START_REF] Goodman | Comparing the Strengths and Difficulties Questionnaire and the Child Behavior Checklist: Is small beautiful?[END_REF].

A chronology of the timing of measurements within ALSPAC and TRAILS is presented in Figure 1.

Relative indices of inequality

We scaled all of the SEP measurements as relative indices of inequality (RII). RIIs enable direct comparison between cohorts of SEP variables as they take account of differences between cohorts in the proportions of the population in the different categories of a socioeconomic variable [START_REF] Mackenbach | Measuring the magnitude of socio-economic inequalities in health: An overview of available measures illustrated with two examples from Europe[END_REF] [START_REF] Harper | Measuring health inequalities[END_REF]. For each indicator of SEP a score between 0 (highest SEP) and 1 (lowest SEP) was assigned to each category based on the proportion of the population above the mid-point in that category. For example, if 10% of the population are in the highest educational category participants in this group are represented by the range 0 to 0.1 and so are allocated the score 0.05 (0.1/2). If 20% of the population are in the next group, middle level education, then this education group is allocated a score 0.20 (0.1 + 0.2/2) and so on. The RII is then obtained by regressing the outcome on each of these SEP scores and is directly interpretable for each SEP indicator used as comparing participants of the lowest SEP (1) with the highest SEP (0).

Analyses

After performing basic descriptive analyses we performed logistic regression analyses separately on ALSPAC and on TRAILS data, with internalising and externalising problems (yes/no, with cut-off around the 85 th percentile) as outcome measures. We chose this cut-off to identify a group with more severe problems, who would be more likely to be in need of or receive mental health care. Using a consistent cut-off in both studies also increased comparability between them as continuous distributions were likely to differ between the two cohorts. In a second step we examined the possibility of moderation by CA. We performed logistic regression analyses stratified by CA tertiles to examine differences in the magnitude of associations between SEP and internalising/externalising problems at different levels of CA. If our hypothesis were correct we would expect to see the weakest association in the group with highest CA and the strongest association in the group with lowest CA. We then performed logistic regression analyses on the complete samples, with an interaction-term of SEP (as a continuous RII variable) with CA (in tertiles) included in the model, as well as the main effects of SEP and CA. We tested possible interactions with likelihood ratio tests between models with and without the interaction terms. These analyses were performed separately with internalising and externalising problems as outcome measures.

For both the main association and the association stratified by tertiles of CA and that including the interaction terms we progressively included additional covariables. I the basic model we adjusted for age and sex only; we then additionally adjusted for maternal depression (which might influence family SEP and be associated with offspring behaviours) and in the final model we mutually adjusted for each of the SEP measurements to examine whether they were independently associated with adolescent behaviours. Finally, analyses with internalising problems as outcome were adjusted for the presence of externalising problems and vice versa, because internalising and externalising problems are known to co-occur and associations of SEP with either one might be confounded by the other due to this.

All analyses were performed only on participants in each cohort who ad complete data on all variables included in any analyses. After excluding participants with missing values on either one or more of the independent and dependent variables a total of 4,041 participants were included from ALSPAC, and a total of 1,703 cases from TRAILS.

Results

There were gradients in the amount of internalising and externalising problems between different education and income groups in both studies (Tables 1 &2). The mean scores and the prevalence of those with internalising or externalising problems were higher with each lower level of mother"s education or household income. The only exception was that mean scores and prevalence of internalising problems were not different between the group of mothers with highest and middle levels of education. Internalising and externalising problems were also higher in each higher tertile of mothers with a history of depressive problems. In general, the crude data from both studies showed that all independent variables were associated with internalising and externalising problems.

The results of the logistic regression analyses in participants with no missing data were largely comparable between the two studies (Table 3). In both cohorts mothers with lower education had children who were more likely to have externalising problems than children of mothers with higher education and this association remained after adjustment for potential confounding factors. Maternal education showed no association with internalising problems. Household income was associated with both internalising and externalising problems. For each study the estimated association was imprecise (i.e. confidence intervals of these estimates were wide).

Given that the point estimates were similar in each study we pooled the results from the two studies to improve precision. Meta-analysis was performed using a fixed effect model (since we had selected measurements from the cohorts that were similar and both cohorts are European populations, and because point estimates for each cohort were similar) using the "meta" command in STATA 7.0 statistical package.

The pooled estimates (combining both studies) of the association of maternal education were RII 1.06; CI 0.82-1.38 and RII 1.65; CI 1.25-2.17 for internalising and externalising behaviours, respectively. The equivalent associations for household income were RII 1.30; CI 0.99-1.71 RII 1.38; CI 1.03-1.84 for internalising and externalising problems, respectively. There was no strong statistical evidence of heterogeneity between the two studies in any of these associations (I 2 statistics 0 to 55% for the four pooled analyses and all p-values >= 0.14).

There was no strong statistical evidence that child"s CA modified associations of parental SEP with childhood behaviour; all p-values for interaction were >=0.36 (Table 4). Whilst some point estimates did look different across the thirds of CA for some associations, these were not consistent across the two cohorts or with each SEP measurement. They were also not consistent with our hypothesis that associations would be strongest in those in the lowest tertile of CA and weakest in those in the highest tertile. The only exception to inconsistencies between cohorts was for household income which appeared positively associated with externalising behaviour in children in the lowest and highest thirds of CA in both cohorts, but inversely associated in those in the middle third of CA. This pattern was not in keeping with our hypothesis and not supported by statistical evidence (p = 0.73 and 0.92, respectively in the two cohorts).

Discussion

Our results showed associations between 1) mother"s education and externalising but not internalising problems and 2) household income and both internalising and externalising problems but no evidence that higher CA of children modified any of these associations.

Our main aim was to examine whether CA modified the association of parental SEP with childhood emotions and behaviours. Specifically, our hypothesis was that children with higher CA would be more resilient to the adverse effects of low SEP on emotional and behaviour problems. There were few consistent patterns between the two cohorts when we examined associations by thirds of CA but nothing in these results to support our hypothesis. The relatively small sample size of each cohort may have limited our ability to test this hypothesis, but if our hypothesis were true even with relatively small sample sizes we would have expected to see greater effects of lower SEP in those with worse CA than in those with better CA and we saw no such patterns at all. Furthermore, it seems likely that any modification will be modest indeed if it cannot be detected in a sample of about 4,000 (ALSPAC).

It is possible that CA does not noticeably protect adolescents from the negative effects of growing up in a low SEP environment on their internalising and externalising problems. The adverse environments associated with lower SEP may be less amenable to modification by CA than other adverse factors that affect children"s mental health problems. Since lower SEP is associated with a wide-range of adverse environmental exposures, including reduced material resources, reduced parenting ability, poorer diet, poor housing conditions, poor neighbourhood amenities and poor education provision, it still remains possible that greater CA may improve resilience to some (but not all) of these but be insufficient to modify their combined effect on internalising and externalising problems. Furthermore, CA might not provide much benefit in situations where adolescents themselves do not have control over the stressful situations such as for instance chronic family socioeconomic hardship. If this were true CA might become a modifier of the association of SEP with mental health problems in later life, without a notable effect in adolescence.

Other factors should be considered for understanding why some adolescents from low SEP families develop internalising or externalising problems whereas others do not. It might be that personality and temperamental factors are more salient interactive factors in relation to affective and behavioural outcomes than a general cognitive indicator such as IQ.

Consistent patterns were observed in data from both cohorts with regard to associations between maternal education and externalising problems, and with regard to household income and internalising and externalising problems. We believe that it is important to investigate associations separately for these two SEP indicators [START_REF] Araya | Education and income: which is more important for mental health?[END_REF] [START_REF] Lahelma | Multiple measures of socioeconomic circumstances and common mental disorders[END_REF]. SEP is a comprehensive multidimensional construct involving financial, social, material and cultural circumstances [START_REF] Lahelma | Multiple measures of socioeconomic circumstances and common mental disorders[END_REF] [START_REF] Bartley | Understanding social variation in cardiovascular risk factors in women and men: the advantage of theoretically based measures[END_REF]. Household income and maternal education reflect different aspects of this construct, and they should therefore not be used interchangeably. Moreover they are likely to predict family processes and adolescent adjustment differently [START_REF] Conger | An interactionist perspective on the socioeconomic context of human development[END_REF]. Lumping specific SEP indicators together into a scale would obscure diverging associations of these with internalising and externalising problems and ignore the fact that they occupy different positions in aetiological developmental pathways.

Associations between household income and adolescent mental health have been reported previously [START_REF] Mccleod | Trajectories of poverty and children"s mental health[END_REF][45] [START_REF] Strohschein | Household income histories and child mental health trajectories[END_REF], than have associations between mother"s education and these outcomes. Our finding that mother"s education is associated with offspring externalising problems is in agreement with findings from previous studies [START_REF] Miech | Low socioeconomic status and mental disorders: a longitudinal study of selection and causation during young adulthood[END_REF] [START_REF] Fergusson | Maternal age and educational and psychosocial outcomes in early adulthood[END_REF].

The lack of association with internalising problems was contrary to previous studies that had demonstrated associations of parental education (not necessarily the mother"s) with internalizing problems in adolescents [45][48][49]. This discrepancy might be explained by our use of mother reports of internalising behaviour rather than self-reports by adolescents as in most previous studies, although most of the other associations reported here (including of maternal depression with outcomes) are consistent with existing literature.

There may be several reasons why adolescents from higher educated mothers have less externalising problems, including more favourable parenting styles (i.e. avoidance of harsh, humiliating and physical punishment), reduced exposure to stressful events within or in the surroundings of the family and less mental health problems in the parents. Potential education-specific explanations that have been suggested for inequalities in mental health reflect human capital more than economic capital, and include fostering of academic achievements of children, and promotion of social competence [START_REF] Conger | An interactionist perspective on the socioeconomic context of human development[END_REF].

Study strengths and limitations

The main strengths of this study are the use of two well characterised cohorts to examine our hypotheses. To our knowledge this hypothesis has not been tested in other cohorts. ALSPAC has a relatively large sample size and the TRIALS cohort provided a means of replicating any findings in order to provide more robust findings.

We could only examine parent-reported measures of internalising and externalising problems. Problem scores based on parent-and child-reports in observational studies correlate only moderately [START_REF] Kraemer | A new approach to integrating data from multiple informants in psychiatric assessment and research: mixing and matching contexts and perspectives[END_REF] and it is commonly recognized that multiple informants contribute unique information that can improve the overall measure of behavioural problems [50][51]. For this particular study it means that the lack of moderation by CA refers to that aspect of adolescent problems observed by the parents (mostly the mother). In other words; adolescents" CA does not seem to modify the association of SEP with behavioural problems of the child as reported by the mother. There is a possibility that results may have been different if the problems had been reported by the children themselves.

Associations presented in this study were adjusted for mother"s history of depression.

Our justification for this is that mother"s depression could influence her educational attainment and household income as well as being associated with offspring behavioural or emotional problems, and could hence be a confounding factor. However, we acknowledge that mother"s depression could also mediate the association of parental SEP with offspring behaviours or emotions (i.e. lower SEP might cause maternal depression which in turn affects childhood behaviours or mood). In both cohorts adjustment for maternal depression did result in attenuation of the associations but we cannot ascertain from our data whether this is due to confounding or mediation.

Missing data in both studies was associated with most of the independent and dependent variables in the study. In ALSPAC, mothers of children for whom data could not be included in this study because of drop-out during earlier phases of the study or (item) non-response on core variables were lower educated on average (Pearson chi-square value 512.8 [df=4], p-value <.001), had higher depression scores (mean depression scores 14.6 and 12.6 respectively, p-value t-test <.001), and had a relatively low family income (Pearson chi-square value 312.7 [df=4], p-value <.001).

Adolescents for whom information on IQ was available but who could not be included in the study because of missing data on covariates had lower IQs on average (mean IQs respectively 101.2 and 106.3, p-value t-test <.001). Adolescents for whom information on internalising and externalising problems at age 13 were available, but who could not be included because of missing data on covariates had higher scores on internalising and externalising problems (mean internalising problems 1.53 and 1.36 respectively, p-value t-test <.001; mean externalising problems 1.30 and 1.21 respectively, p-value t-test <.001). In TRAILS, non-participants at baseline were more likely to be from lower SEP families. Based on teacher ratings, there were no indications that non-participants at baseline had higher internalising or externalising scores [START_REF] Huisman | Cohort profile: The Dutch "TRacking Adolescents" Individual Lives" Survey; TRAILS[END_REF]. Adolescents who could not be included in this analysis because of missing data on covariates had on average lower IQ scores (mean IQs respectively 92.5 and 98.6, p-value t-test <.001), and had higher externalising problems scores at baseline but not higher internalising problem scores (mean externalising problems 0.26 and 0.24 respectively, p-value t-test <.001), had lower educated mothers (Pearson chi-square value 64.5 [df=4], p-value <.001) and were from lower income families (Pearson chi-square value 127.4 [df=8], p-value <.001) .

Whilst we cannot test this possibility, missing data would importantly bias our results only if the associations that we have found were in the opposite direction in those excluded because of missing data. Likewise, the failure to prove our hypothesis regarding the moderation of familial SEP associations with adolescent behaviours would be incorrect if in those with missing data there was a marked moderating effect of CA on SEP. Nonetheless we can think of no reasons why this would be the case.

Conclusion

It is important to theorise and test mechanisms through which multiple risk factors work together in the emergence of internalising and externalising problems in the early life course [START_REF] Essex | Exploring risk factors for the emergence of children"s mental health problems[END_REF]. We tested whether CA moderated the association of parental SEP with adolescent problem behaviours, because this hypothesis relates closely to stress-resilience models of early life development. We did not find support for our hypothesis in this study. Future studies should examine whether findings differ if child, rather than parental, reports of behaviours or emotions are used. Finally, it is also worth mentioning that CA might become a more important factor in relation to resilience against environmental stress in later life and this should be examined in cohorts that have relevant data at older ages.

Tables

Table 1 ;

 1 Descriptive statistics and distribution of internalising (emotional) and externalising (behavioural) problems; ALSPAC

			Internalising		Externalising
		N	Mean (SD)	Prevalence (%)	Mean (SD)	Prevalence (%)
	Total (complete cases)	4041	1.36 (1.66)	19.8	1.21 (1.40)	15.3
	Mother's educational level
	Low (CSE or no education)	311	1.52 (1.92)	22.8	1.33 (1.50)	18.1
	Middle (vocational or O level)	1735	1.43 (1.69)	21.0	1.27 (1.45)	16.9
	High (A level or degree)	1995	1.27 (1.59)	18.3	1.13 (1.34)	13.4
	Household income
	Lowest	1528	1.48 (1.79)	21.4	1.35 (1.53)	17.9
	Middle	1342	1.32 (1.65)	19.7	1.12 (1.29)	14.4
	Highest	1171	1.25 (1.49)	17.8	1.11 (1.33)	13.0
	Cognitive ability (IQ)
	Lowest tertile	1338	1.56 (1.76)	23.2	1.40 (1.54)	19.3
	Middle tertile	1356	1.38 (1.68)	21.0	1.22 (1.40)	15.9
	Highest tertile	1347	1.14 (1.51)	15.2	1.00 (1.22)	10.7
	Maternal depression (EPDS)
	Lowest tertile	1468	1.09 (1.48)	14.9	0.98 (1.23)	10.8
	Middle	1256	1.29 (1.54)	18.1	1.14 (1.33)	13.9
	Highest tertile	1317	1.73 (1.89)	27.0	1.52 (1.59)	21.6

Table 2 ;

 2 Descriptive statistics and distribution of internalising (emotional) and externalising (behavioural) problems; TRAILS

			Internalising		Externalising
		N	Mean (SD)	Prevalence (%)	Mean (SD)	Prevalence (%)
	Total (complete cases)	1703	.20 (.18)	15.1	.17 (.18)	18.0
	Mother's educational level
	Low (≤ Lower secondary)	589	.21 (.19)	15.8	.20 (.20)	22.9
	Middle (Higher secondary)	612	.21 (.19)	16.2	.17 (.18)	18.0
	High (Higher vocational/university)	502	.19 (.18)	13.1	.13 (.15)	12.2
	Household income
	Lowest	688	.22 (.19)	16.9	.19 (.19)	20.5
	Middle	525	.21 (.18)	15.6	.17 (.18)	18.9
	Highest	490	.17 (.17)	12.2	.13 (.16)	13.5
	Cognitive ability (IQ)
	Lowest tertile	585	.21 (.20)	17.4	.21 (.22)	23.8
	Middle tertile	657	.19 (.18)	12.0	.16 (.17)	15.7
	Highest tertile	461	.20 (.18)	16.7	.14 (.14)	13.9
	Maternal depression
	No	1239	.18 (.17)	12.2	.15 (.17)	15.1
	Yes	101	.25 (.19)	22.8	.20 (.21)	19.8
	Yes + had treatment/medication	363	.27 (.21)	23.1	.23 (.21)	27.3

Table 3 ;

 3 Associations of mother"s educational level and household income with internalising and externalising problems;

	Relative index of inequalities (RII)
		Internalising			Externalising
		Model 1	Model 2	Model 3	Model 1	Model 2	Model 3
	ALSPAC
	Mother"s educational	1.30	1.18	1.10*	1.79	1.58	1.42 §
	level	(0.98-1.72)	(0.89-1.56)	(0.81-1.49)	(1.31-2.44)	(1.15-2.17)	(1.01-1.99)
	Household income	1.40	1.25	1.21 ‡	1.80	1.25	1.36 †
		(1.05-1.86)	(0.94-1.67)	(0.88-1.65)	(1.31-2.47)	(0.94-1.67)	(0.96-1.92)
	TRAILS
	Mother"s educational	1.24	1.15	0.97*	2.65	2.49	2.21 §
	level	(0.78-1.97)	(0.72-1.84)	(0.58-1.61)	(1.72-4.08)	(1.61-3.85)	(1.37-3.54)
	Household income	1.77	1.61	1.63 ‡	2.17	1.97	1.42 †
		(1.06-2.94)	(0.96-2.69)	(0.93-2.84)	(1.34-3.52)	(1.21-3.21)	(0.84-2.40)

Note: Model 1 = bivariate; Model 2 = adjusted for maternal depression and sex; Model 3 = adjusted for maternal depression, sex and other socioeconomic indicator; * Pooled estimate: 1.06 (0.82-1.38), § Pooled estimate: 1.65 (1.25-2.17), † Pooled estimate: 1.38 (1.03-1.84), ‡ Pooled estimate: 1.30 (0.99-1.71)

Table 4 .

 4 Associations of mother"s educational level and household income with internalising and externalising problems, stratified

	by tertile of cognitive ability
			Internalising		Externalising
			Mother"s	Household	Mother"s	Household
			educational	income	educational level	income
			level
	ALSPAC Cognitive ability
		Lowest tertile	1.22 (0.72-2.08) 1.18 (0.70-2.00)	1.43 (0.81-2.54)	1.52 (0.86-2.69)
		Middle tertile	0.55 (0.32-0.93) 1.08 (0.64-1.81)	1.00 (0.56-1.79)	0.68 (0.38-1.21)
		Highest tertile	1.20 (0.65-2.21) 1.14 (0.62-2.10)	0.91 (0.45-1.84)	2.36 (1.18-4.75)
		p-value interaction	.42	.41	.88	.92
		Likelihood ratio	-4.50		-0.11
	TRAILS	Cognitive ability
		Lowest tertile	0.65 (0.28-1.51) 2.09 (0.77-5.62)	1.10 (0.51-2.36)	1.65 (0.69-3.97)
		Middle tertile	2.65 (1.06-6.57) 1.50 (0.56-4.06)	2.89 (1.20-6.03)	0.81 (0.35-1.87)
		Highest tertile	0.41 (0.13-1.27) 1.42 (0.55-3.64)	1.93 (0.64-5.82)	2.34 (0.78-7.01)
		p-value interaction	.78	.36	.37	.73
		Likelihood ratio	-2.56		-1.63

Measurement time points within ALSPAC and TRAILS

	Appendix Table 1. SDQ and CBCL items included in the study		him/herself
	ALSPAC -SDQ †		TRAILS -CBCL ‡	29. Is underactive, slow moving or lacks
					energy
	Internalising	1. Has often complained about	Internalising		1. There is little that he/she likes 30. Is unhappy, sad or depressed
	problems	headaches, stomach aches or	problems		31. Withdrawn, does not get into contact
		sickness			with others
		2. Has many worries, often seems			2. Cries a lot 32. Worries
		Mother"s education, worried		WISC-III, child	SDQ, child age 13
	Externalising	mother"s depression, during pregnancy 3. Is often unhappy, down-hearted, 1. Has often had temper tantrums	Externalising	age 8 yrs 3. Is afraid of animals, situations, places yrs 1. Drinks alcohol without permission of
	problems	tearful or hot tempers	problems		an adult
	ALSPAC
		4. Is nervous/clingy in new 2. Is generally obedient, usually			4. Is afraid to go to school 2. Argues a lot
		situations, easily loses confidence does what adults request (recoded)
		Income, child age 4 yrs 5. Has many fears, is easily scared 3. Often fights or bullies other		5. Fears he/she might think or do 3. Cruelty, bullying or meanness to
		children/teenagers			something bad others
		4. Often lies or cheats			6. Feels he/she needs to be perfect 4. Demands a lot of attention
		5. Steals from home, school, or	Mother"s education, income, WISC-R, mother"s depression; mean age child 11.1 yrs 7. Feels or complains that no one loves 5. Destroys his/her own things
		elsewhere			him/her
	TRAILS				8. Feels worthless or inferior 6. Destroys things of others
					CBCL, T2, mean age 9. Rather is alone than with others 7. Is disobedient at home
					child 13.6 yrs 10. Is nervous, high-strung or tense 8. Is disobedient at school
					11. Has nightmares 9. Does not seem to feel guilty after
					12. Has constipations, holds faeces misbehaving
					13. Feels dizzy 10. Does not obey rules at home, in
					14. Is overtired school, or elsewhere
					15. -21. Has physical problems without 11. Gets into many fights
					a known medical cause: aches or pains, 12. Hangs around with others who get
					headaches, nausea, problems with eyes, into trouble
					rashes or other skin problems, stomach 13. Lies or cheats
					aches or cramps, vomiting 14. Physically attacks others
					22. Feels too guilty 15. Prefers being with older kids
					23. Too fearful or anxious 16. Runs away from home
					24. Refuses to talk 17. Screams a lot
					25. Is taciturn 18. Sets fires
					26. Is self-conscious or easily 19. Has sexual problems
					embarrassed 20. Steals from home
					27. Is shy or timid 21. Steals from other places
					28. Talks about wanting to kill 22. Is stubborn, sullen or irritable
					37

Acknowledgements

We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC. DAL"s contribution to this work was part of her work on a UK Economic and Social Research Council large grant (RES-060-23-0011). We are extremely grateful too to all adolescents, their parents, teachers and siblings who participated in the TRAILS study and to everyone who worked on this project and made it possible. Participating centers of TRAILS include various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Trimbos Institute, all in the Netherlands. Principal investigators are Prof. Dr. J. Ormel (University Medical Center Groningen) and Prof. Dr. F.C. Verhulst (Erasmus University Medical Center). TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; Zon-Mw Risk Behavior and Dependence grants 60-60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, an GBMaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), and the participating universities.

The work presented here is that of the authors and not necessarily any of the funding bodies. The authors had full access to the data and the funding bodies did not interfere with data analysis or conclusions. This publication is the work of the authors and Martijn Huisman will serve as guarantor for the contents of this paper. This research was specifically funded by NWO Veni grant MaGW 541-08-019.