Tytti Solantaus
email: tytti.solantaus@thl.fi

E Juulia Paavonen

Sini Toikka

Raija-Leena Punamäki

Preventive interventions in families with parental depression: Children's psychosocial symptoms and prosocial behaviour

Keywords: Parental depression, child mental health, preventive intervention, randomized trial

Objective: The aim is to document the effectiveness of a preventive family intervention (Family Talk Intervention, FTI) and a brief psychoeducational discussion with parents (Let's Talk about the Children, LT) on children's psychosocial symptoms and prosocial behaviour in families with parental mood disorder, when the interventions are practiced in psychiatric services for adults in the Finnish National health service. Method: Patients with mood disorder were invited to participate with their families. Consenting families were randomized to the two intervention groups. The initial sample comprised 119 families and their children aged 8-16. Of these, 109 completed the interventions and the baseline evaluation. Mothers and fathers filled out questionnaires including standardized rating scales for children's symptoms and prosocial behaviour at baseline and at four, ten and eighteen months post intervention. The final sample consisted of parental reports on 149 children with 83 complete data sets. Results: Both interventions were effective in decreasing children's emotional symptoms, anxiety and, marginally, hyperactivity and in improving children's prosocial behaviour. The FTI was more effective than the LT on emotional symptoms particularly immediately after the intervention, while the effect of the LT emerged within a longer interval. Conclusions: The study supports the effectiveness of both interventions in families with depressed parents.

The Family Talk Intervention is applicable in cultural settings other than the USA. Our findings provide support for including preventive child mental health measures as part of psychiatric services for mentally ill parents.

Introduction

Parental depression has extensive consequences on family life and on offspring social adjustment and mental health in childhood and in later life, depression and anxiety being the major psychiatric problems [START_REF] Beardslee | Children of Affectively Ill Parents: A Review of the Past 10 Years[END_REF][START_REF] Goodman | Children of depressed parent. Mechanisms of risk and implications for treatment[END_REF][START_REF] Weissman | Offspring of depressed parents: 20 years later[END_REF]. It is profoundly a family matter as depression changes one's behaviour and emotional presence.

Insecurity, withdrawal and worry begin to characterize family relationships and negative family interactions have been documented to mediate between parental and child mental health problems [START_REF] Cummings | Security, emotionality, and parental depression[END_REF][START_REF] Cummings | Maternal depression and child development[END_REF][START_REF] Downey | Children of Depressed Parents: An Integrative Review[END_REF][START_REF] Leinonen | Parental mental health and children's adjustment: the quality of marital interaction and parenting as mediating factors[END_REF][START_REF] Pilowsky | Family discord, parental depression, and psychopathology in offspring: 20-year follow-up[END_REF][START_REF] Rutter | Commentary: Some processes and focus considerations considering effects of parental depression on children[END_REF][START_REF] Solantaus-Simula | Children's responses to low parental mood. II: associations with family perceptions of parenting styles and child distress[END_REF].

The intergenerational transfer of psychiatric disorders and the present and predicted high depression rate among adults [24] have elicited an urgent need for promotion of child development and prevention of children's psychosocial symptoms and disorders as part of the services for families with parental depression [25,[START_REF] Reiss | Transmission and treatment of depression[END_REF] [START_REF]Reducing risks for mental disorders: frontiers for preventive intervention research[END_REF]25]. Fortunately, several preventive interventions for children with family adversity have been developed and found efficacious in randomized controlled trials [START_REF] Beardslee | A family-based approach to the prevention of depressive symptoms in children at risk: evidence of parental and child change[END_REF][START_REF] Beardslee | Long-term effects from a randomized trial of two public health preventive interventions for parental depression[END_REF][START_REF] Clarke | A randomized trial of a group cognitive intervention for preventing depression in adolescent offspring of depressed parents[END_REF][START_REF] Garber | Prevention of Depression in At-Risk Adolescents. A randomized controlled trial[END_REF]26,[START_REF] Sandler | The family bereavement program: efficacy evaluation of a theory-based prevention program for parentally bereaved children and adolescents[END_REF].

In Finland, the countrywide Effective Child & Family (EC&F) Programme was launched in 2001 to develop, study and implement preventive child mental health interventions in health services treating adult patients with mental health disorders [36]. It is a countrywide research, training and implementation programme for health and social services to attend to the needs of children and families with parental mental health and substance use disorder. The US originated Family Talk Intervention was adopted and a brief psychoeducational discussion with parents (Let's Talk about Children, LT) was developed for the EC&F Programme as well as a guide book for parents. This study belongs to the research arm of the EC&F Programme.

The Family Talk Intervention (FTI) aims to promote parenting and child development and prevent children's psychiatric problems in families with parental depression [START_REF] Beardslee | Response of Families to Two Preventive Intervention Strategies: Long-Term Differences in Behavior and Attitude Change[END_REF]. It is designed to enhance family communication and understanding concerning depression and to support interpersonal relationships in the family and children's social life outside the family, which have all been documented to build up family and child strengths and resilience [START_REF] Beardslee | Resilient adolescents whose parents have serious affective and other psychiatric disorders: importance of self-understanding and relationships[END_REF]25].

The efficacy of the FTI has been studied in comparison with a lecture intervention for parents in a randomized setting in the USA [START_REF] Beardslee | A family-based approach to the prevention of depressive symptoms in children at risk: evidence of parental and child change[END_REF][START_REF] Beardslee | Sustained Change in Parents Receiving Preventive Interventions for Families With Depression[END_REF][START_REF] Beardslee | Long-term effects from a randomized trial of two public health preventive interventions for parental depression[END_REF]. At the 4.5-year follow up the FTI group showed, relative to the lecture group, positive changes in family communication and children's understanding concerning parental depression. In addition, both interventions were associated with positive changes in family functioning and a decrease in children's depressive symptoms. The FTI has also been studied in African American and Latino populations with similar results [START_REF] Angelo | Adaptation of the preventive intervention program for depression for use with predominantly low-income Latino families[END_REF][START_REF] Podorefsky | Adaptation of preventive interventions for a low-income, culturally diverse community[END_REF]. However, recent research has shown that parental treatment and alleviation of parental symptoms is also reflected in decrease of children's symptoms [20,[START_REF] Kennard | Maternal depressive symptoms in pediatric major depressive disorder: relationship to acute treatment outcome[END_REF]39], while this was not controlled in the US studies concerning the FTI. Demonstration of efficacy is not enough for large scale implementation. Efficacy results are elicited in settings, which are optimal and highly controlled in order to ascertain the intervention impact on the expected outcomes. Efficacy studies are a test of the theoretical and empirical underpinnings of the interventions. Intervention delivery is carried out by highly trained experts, who enter the family or patient care only to carry out the given intervention. Furthermore, the interveners are usually given continuous supervision by the intervention developer to ensure adherence to the intervention protocol.

Concern has been expressed about evidence-based interventions not being implemented on a wide-scale basis and also about lack of effectiveness findings in public health services [25]. If an intervention is to be implemented on a large scale, it also needs to stand the test of 'real world' -those circumstances where it will be carried out when taken to scale. It means being practiced as part of standard services, i.e. (1) the intervention is carried out by grass root practitioners rather than outside experts, (2) the practitioners have been trained and they are experienced in carrying the intervention out as part of their services and [START_REF] Beardslee | Resilient adolescents whose parents have serious affective and other psychiatric disorders: importance of self-understanding and relationships[END_REF] there is no such supervision, which is not intended to be part of the normal intervention practice. This is, indeed, the setting in our trial and this study will contribute its share to the understanding of taking preventive measures to standard services on a large scale.

In this paper, we study the effectiveness of the FTI [START_REF] Beardslee | A family-based approach to the prevention of depressive symptoms in children at risk: evidence of parental and child change[END_REF][START_REF] Beardslee | Response of Families to Two Preventive Intervention Strategies: Long-Term Differences in Behavior and Attitude Change[END_REF] and the LT. Both interventions have been previously reported to be safe and feasible in Finland, and parents reported increased understanding in the family, enhanced parenting, and feeling better immediately after the interventions [START_REF] Solantaus | Safety, feasibility and family experiences of preventive interventions for children and families with parental depression[END_REF]. Based on these findings and earlier research on the FTI [START_REF] Beardslee | A family-based approach to the prevention of depressive symptoms in children at risk: evidence of parental and child change[END_REF][START_REF] Beardslee | Long-term effects from a randomized trial of two public health preventive interventions for parental depression[END_REF], we hypothesized that both interventions are associated with a positive impact on children's psychosocial symptoms and a promotion impact on children's prosocial behaviour, but more so in the FTI.

Methods

Study Design

This is a cluster, randomized, controlled intervention trial with approval of the ethical committee of the Hospital District of Helsinki and Uusimaa. The sample was studied at baseline (BL), and parental reports collected at 4, 10 and 18 months.

The Interventions

The FTI begins with two Parent Sessions covering personal and family history and psychoeducation about depression and resilience. A Child Session with each child follows. Children's psychosocial situation and their family experiences are mapped and possible questions concerning parental mental illness elicited. In the Planning Session, parents discuss with the clinician how to respond to children's questions, how to talk about depression with all family members present and how to best deal with possible family problems. In the Family Session the parents put mental illness into words for their children and answer children's questions with the clinician's help. Finally, the intervention is reviewed and plans for the future discussed in the Follow-Up Session with parents. In a family with one child, there are 6 sessions. The session number increases with the increasing child number.

The LT is a child-focused discussion conducted with the patient and possibly his/her partner to assess the child's situation and to provide information on how parents can support their children. The minimum discussion time was 15 minutes and the maximum two 45-minute sessions in the trial. Both interventions were manualized.

In both interventions, the parents were given a self help guide called How Can I Help My Children, A Guide Book for Parents with Mental Health Problems [START_REF] Solantaus | Miten autan lastani? Opas vanhemmille, joilla on mielenterveyden ongelmia[END_REF] and a standard information booklet about depression. If there was a need for other services, i.e. child psychiatric or social services, the families were helped in accessing them.

There was no practice as usual -group. Children's risks are so high in families with diagnosed parental depression that a no-discussion condition would have been unethical. The Child Welfare Act in Finland further provides that if a parent receives mental health services, the needs for care and support of dependent children are to be taken care of. The LT was developed with a minimal format so as to be as close as possible to practice as usual while also meeting the minimum requirements of the law.

Participants and procedure

Sixteen health care units in eight regional national health organizations located in different parts of the country participated in the study. Patients diagnosed in their medical records and currently treated for any mood disorder defined in ICD-10 were invited to participate in the study with their partners, if they had at least one child aged 8 -16 years not being treated for psychiatric disorder. Parental psychotherapy and comorbidity with both psychiatric and medical illness were allowed. However, schizophrenia and life threatening stage of a somatic disease of the parent or child, families with ongoing family therapy, custody dispute and immediate need for involvement of child protection services were excluded from the study.

Clinicians in the participating mental health units provided both verbal and written information of the study to the patients. Rights to refuse or later withdraw from the study were pointed out to the family members.

Informed consent was obtained from parents and children over fifteen years of age, which is according to Finnish regulations. The parents were instructed to inform also younger children of their rights to refuse and withdraw from the study. Based on the clinicians' records, it was estimated that 40-45% of all eligible families consented to the study. As reported in more detail elsewhere [START_REF] Solantaus | Safety, feasibility and family experiences of preventive interventions for children and families with parental depression[END_REF], the major reasons for refusals were due to the patients themselves (about 35%) ("I am feeling better and want to put it behind", " I am not interested") and other family members not being willing to participate (about 40%).

The consenting families were randomized into two groups using computerized block randomization with block sizes 6-8. The clinicians carried out the interventions with their own patients, if the patient was randomized into the intervention type the clinician was trained to do. Otherwise a colleague trained in that particular intervention carried it out.

Measures

The Beck Depression Inventory (BDI) is a self-report measure to study parents' depressive symptoms [START_REF] Beck | An inventory for measuring depression[END_REF].

There are 21 questions for measuring depressed feelings such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms. The responses are scored from 0 to 3, and a total score is calculated. The Spielberger State Anxiety Inventory (STAI) was used to measure parental anxiety [START_REF] Spielberger | The state-trait anxiety inventory[END_REF]. It consists of 20 positively (e.g. 'I am calm') or negatively worded items ('I am nervous and restless') items that are rated on a four-point scale (0=not at all to 3=completely) and a total score is calculated. These scales were filled in at each time point.

Children's psychological symptoms and prosocial behaviour were measured by the 25-item Strengths and Difficulties Questionnaire (SDQ) which has good psychometric properties [START_REF] Bourdon | The Strengths and Difficulties Questionnaire: U.S. normative data and psychometric properties[END_REF][START_REF] Goodman | The Strengths and Difficulties Questionnaire: A research note[END_REF]. The problem scale consists of 20 symptoms describing emotional, hyperactivity, conduct and peer problems. Both parents evaluated the fitness of the descriptions on a 3-point scale (0 = not at all, 1 = somewhat, 2 = yes, fit well).

Four subscale scores, and a total score were constructed separately for mothers, fathers and children.

Prosocial behaviour were assessed by the five-item scale in the SDQ. Children's anxiety was assessed by a five-item version of Screen for Child Anxiety Related Emotional Disorders (SCARED) [START_REF] Birmaher | Psychometric properties of the screen for child anxiety related emotional disorders (SCARED): a replication study[END_REF]. Parents rated the frequencies of children experiencing each symptom on a 3-point scale (0 =almost never, 1= sometimes, 3=often). A total score was obtained. Parental data reported comes from mothers and if the mother was missing, from the father.

The fidelity of the interventions was ascertained by logbooks filled out by practitioners. For the FTI, the logbooks listed the manualized topics for discussion and the practitioners marked down choices 'Discussed, yes/no'. Also the dates, participants and session types were documented in both interventions. According to Beardslee, as reported in [START_REF] Solantaus | Safety, feasibility and family experiences of preventive interventions for children and families with parental depression[END_REF], the FTI is carried out with fidelity if the family session (the second last session) is carried out. The LT was carried out with fidelity, if children were discussed for at least 15 1). The initial refusal rate was 9.2%, and dropout rates were 24.6% (LT) and 34.0% (FTI) at 4 months and 29.8% (LT) and 26.4% (FTI) at 10 months and 22.8% (LT) and 24.5% (FTI) at 18 months (compared with the number of intervention completers at BL). The final sample consisted of parental reports on 149 children with 83 (43 LT, 40 FTI) having complete data sets.

There were no significant differences in the response rates between the two intervention groups (all p's >0.157) and the patient's gender either did not affect the response rates (all p's >0.108). The drop out analyses revealed that patient's lower level depression (p=0.047) and anxiety (p=0.031) at baseline, but not children's psychiatric symptom levels (all p's > 0.07) predicted participation in the forthcoming data collection rounds.

Statistical methods

We first studied whether there were any significant baseline group differences using t-test for independent samples for continuous variables and X 2 tests for categorical variables. Next we compared group differences in the changes of the symptom and behaviour scores using repeated measures ANOVA (BL vs. 4 mo, BL vs. 10 mo and BL vs 18 mo). Because parental depression can modify the findings, we statistically controlled for the patient's baseline BDI as well as its change over the corresponding time period in the models. To compare longitudinally the average change in each group and to take into account the dependence between the siblings, we used linear mixed effects models with two random effects (for dependence over time and over siblings). However, due to the small number of families with more than one child, the intraclass correlation could not be estimated in every model. Whenever it could be estimated, the p-values changed only slightly, suggesting that the models are robust and that familial clustering had only a minimal impact on the findings. Final models control for dependence over time assuming autoregressive covariance structure that provided the best fit of the models. All the response variables were continuous and they were skewed only to some extent, which means that the normality assumptions of the parametric tests were not violated. None of the unequally distributed baseline variables affected the interpretation of the models.

Results

The intervention groups were similar in their baseline demographic factors, except for mothers' lower education and the larger number of divorced/separated families in the FTI (Table 1). The psychiatric characteristics of the participating parents were similar in both intervention groups. Of the mothers, 67 had a diagnosis of unipolar depression (33 in the LT, 34 in the FTI), eight had a diagnosis of bipolar depression (5 in the LT, 3 in the FTI) and 4 had a diagnosis of anxiety disorder with depression (2 in the LT, 2 in the FTI).

There were also two mothers whose diagnoses were not reported. Of the fathers, 26 had a diagnosis of unipolar depression (13 in the LT, 13 in the FTI) and 6 had a diagnosis of bipolar depression (3 in the LT, 3 in the FTI). There were no statistical significant differences between the two intervention groups (all p's > 0.479). Most patients had had symptoms at least for a year, which reflects the well-known chronicity of depression.

The logbooks filled out by clinicians showed that both interventions were carried out with fidelity. All Family Talk Interventions included all of the different session types. The LT was carried out in one full session in 76% and in two sessions in 24% of the families.

As reported in Table 2 and shown in Figure 2, we found that children's emotional symptoms (SDQ) generally decreased during the follow-up (p=0.036) and time * group -interaction effect (p = 0.040) indicated differences between the FTI and LT intervention when controlling for the patient's depressiveness at baseline and its change over time. Repeated ANOVA specified that the greatest decrease in emotional symptoms happened in the FTI from baseline to four months, and in the LT from four to ten months, while there were no group differences from ten to eighteen month follow-up. Furthermore, children's anxiety decreased significantly in both intervention groups (p = 0.003) and hyperactivity tended to decrease although the change did not reach statistical significance (p = 0.072). Finally, children's prosocial behaviour improved in both groups (p < 0.001), Again, the repeated ANOVA specified that the change emerged in the FTI group between baseline and four months, while it happed in the LT between ten and eighteen months. The results were similar when we did not covariate for the parental depression level.

DISCUSSION

Our concern is the transfer of mental illness from generation to generation and our interest is to learn how to contribute to breaking the cycle in everyday clinical practice in the health care system. We studied the effectiveness of two interventions, the more extensive Family Talk Intervention (FTI) and a short child focused Let's Talk about Children discussion (LT), when the interventions were carried out in psychiatric health services for adults. Both interventions were coupled with a guide book for parents.

As hypothesized, both interventions were associated with children's mental health and the effects could be still documented at 1,5 year follow up. The main aim of the interventions is to prevent the rise of children's psychosocial symptoms, and thereby eventually prevent outbreak of depressive and anxiety disorders in the offspring. The interventions did not only prevent the rise in children's symptoms, but even led to a decrease in these symptoms in both groups. As we were able to control for the parents' depression, these positive changes were not due to alleviation of parental depression, which is known to be associated with symptom reduction in children [20,[START_REF] Kennard | Maternal depressive symptoms in pediatric major depressive disorder: relationship to acute treatment outcome[END_REF]39].

Children's prosocial behaviour improved and emotional symptoms, anxiety and, marginally, hyperactivity decreased both in the FTI and the LT, while the FTI was more effective in reducing emotional symptoms relative to the LT. The higher effectiveness of FTI was time-dependent.

It is noteworthy that the positive changes in the FTI tend to happen during the first four months, while the change in the LT takes more time. The FTI involves the whole family and also directly children and the intended family process is initiated during the intervention itself. In contrast, the impact of the LT on children is mediated totally through parents. Parents are given information, which they most likely process within themselves before they involve children, and the family process itself is likely to be slower.

Our study is the first one to document the effectiveness of the FTI over and above the control intervention.

The US and Finnish studies have methodological differences which may explain this. Our study was a questionnaire study, while the Beardslee et al. study was interview-based. These discussions with the families may have increased the effectiveness of the lecture group. They might also predispose to report bias, i.e. parents may less openly express negative views on the interventions, when they are interviewed in person. The second difference concerns the study settings. As our study was carried out in real-world conditions, the interventions were imbedded in the patient's normal treatment process. Therefore, the interveners may have been able to link the psycho-educational material and intervention process more closely to the patient's and the family's personal experiences and life situation. This is, indeed, the aim in the FTI and might contribute to its effectiveness in our trial. The effects of the FTI might be even stronger in real-world than in highly controlled efficacy trials.

Both interventions were related to a significant decrease in children's anxiety and marginal decrease in hyperactivity. Anxiety is linked with experiences of threat and insecurity about the present and the future, which often characterize families with parental mental illness [START_REF] Cummings | Security, emotionality, and parental depression[END_REF][START_REF] Cummings | Maternal depression and child development[END_REF]. Hyperactivity in turn can be understood as a behavioural response to the fear, worry and relationship problems documented in families with parental depression [START_REF] Ashman | Trajectories of maternal depression over 7 years: relations with child psychophysiology and behavior and role of contextual risks[END_REF] . Hyperactivity can evoke punitive parenting practices thus accelerating family problems.

The main focus of our preventive interventions is to help family members to come together to master the family situation and to find strategies to deal with problems in a constructive way. This might build up a sense of security for all family members. We have, indeed, previously reported that a majority of parents in both interventions experienced increased confidence in children's and family future and a decrease in their worries [START_REF] Solantaus | Safety, feasibility and family experiences of preventive interventions for children and families with parental depression[END_REF]. The present findings suggest that our interventions are successful in actually alleviating children's problems and enhancing promotive behaviour.

Promotion of protective factors is an important goal in preventive and promotion efforts. Prosocial behaviour provides means for children to solve interpersonal problems constructively and to strengthen their relationships. Connectedness to peers and family is essential for healthy development [25] and one of the key protective factors for children in families with parental mental health problems [START_REF] Beardslee | Resilient adolescents whose parents have serious affective and other psychiatric disorders: importance of self-understanding and relationships[END_REF]. Both interventions promoted in the long run children's prosocial behaviour and thereby our finding suggests that they have not only preventive but also promotion capacity.

The relative similarity in the effectiveness of the intensive, family based FTI and the brief parent based LT is relevant for preventive policies. The costs of the FTI exceed those of the LT, but the FTI brings more immediate improvements to the children. Families with depressed parents are not a homogeneous group, but differ in their resources and vulnerabilities. Ideally depressed patients with children should be offered preventive alternatives tailored to their needs. Further research should shed light on the mechanisms of positive change and identify families who benefit from one intervention rather than from the other. These questions are important for clinical practice as well as for further intervention development.

It has been argued that intervention development should include its applicability in other than the original culture [START_REF] Olds | Programs for parents of infants and toddlers: recent evidence from randomized trials[END_REF]. The FTI has been studied in middle class, predominantly white population [START_REF] Beardslee | A family-based approach to the prevention of depressive symptoms in children at risk: evidence of parental and child change[END_REF][START_REF] Beardslee | Long-term effects from a randomized trial of two public health preventive interventions for parental depression[END_REF] as well as African American and Latino populations in the USA with favourable results [START_REF] Podorefsky | Adaptation of preventive interventions for a low-income, culturally diverse community[END_REF][START_REF] Podorefsky | Adaptation of Preventive Interventions for a Low-Income, Culturally Diverse Community[END_REF]. Our positive findings in the Finnish health care provide strong support for the applicability of the FTI in new cultural settings, albeit within the Western cultural sphere.

Apart from the actual effectiveness findings, the study provides evidence that attending to the preventive child mental health needs is possible and effective in services for adults. The preventive interventions were implemented in the Finnish National health service and carried out as part of the treatment protocol for adult patients with mood disorder. The Effective Child & Family Programme [36] thus presents a new approach, even a paradigm change for psychiatric services by including promotion of parenting and prevention of child mental health problems in the treatment for the adult psychiatric patient.

Strengths and limitations of the study

The strength of our study is in its nature as a true effectiveness study carried out by 'lay' practitioners in the national health services. As such it forms the next step [START_REF]Reducing risks for mental disorders: frontiers for preventive intervention research[END_REF] from the highly controlled efficacy studies in the process of intervention development and implementation.

There are also limitations, the main concern being the initial refusal rate (about 55-60%) and drop out rate during the study (about 25%). It is common that prevention trials report high refusal and attrition rates [START_REF] Braver | Maximising both internal and external validity in longitudinal true experiments with voluntary treatments. The "combined modified" design[END_REF][START_REF] Olds | Programs for parents of infants and toddlers: recent evidence from randomized trials[END_REF]. Large fraction of those who have initially consented, never participate in the intervention or withdraw during the study [25]. It seems more difficult to promote subject involvement and adherence in preventive than in treatment trials. This is understandable as preventive interventions deal with predicted but not present problems. Furthermore, many subjects in risk groups never develop problems and their refusal to participate in preventive interventions can be considered rational. In addition, our study involved whole families. In family approaches, all family members have to consent to the study, which lowers the consent rate compared to interventions for individuals. This was also seen in our study.

On the other hand, in some families, the depression itself might contribute to lack of energy and motivation to participate. This was the case also in our study, since the initial level of depression and anxiety was higher in those who withdrew during the study than in those who persisted. It may interfere in the generalizability of our findings for parents with severe symptoms. Furthermore, the effectiveness design in our study might have also contributed to the refusal and attrition.

Our interventions were imbedded in the patients' normal clinical visits and carried out by the health care staff, while in efficacy studies, e.g. the Beardslee et al. study [START_REF] Ashman | Trajectories of maternal depression over 7 years: relations with child psychophysiology and behavior and role of contextual risks[END_REF][START_REF] Beardslee | Response of Families to Two Preventive Intervention Strategies: Long-Term Differences in Behavior and Attitude Change[END_REF] the families receive visits from outside experts coming from a prestigious research centre. This might raise the families' motivation and it presents one further difference between a real-world effectiveness and a controlled efficacy study. Finally, we offered no pay for participation, which is the standard in Finland.

A further limitation is the lack of a control, no-interference group. The LT was a very brief intervention, but it did depart from earlier practice in that children were systematically discussed and parents received the self help booklet [START_REF] Solantaus | Miten autan lastani? Opas vanhemmille, joilla on mielenterveyden ongelmia[END_REF]. A no-interference control group would have been needed to document a true prevention effect, i.e. a possible rise of symptoms in the control group with no change in the study group.

The decrease of symptoms presented here is a treatment rather than prevention effect, although it might prevent the development of full blown disorder in a longer follow-up.

Finally, child reports should also be studied. It is important to learn about children's own experiences of their well being and family. Multiple informants also contribute to a more comprehensive understanding of family dynamics.

Conclusions

Our study is the first to document the effectiveness of preventive child mental health interventions when taken to psychiatric services for adults in a national health care system. The FTI and the brief LT stand the test of 'real world', and can be taken to scale. The FTI can be adopted across cultural boundaries at least within the Western cultural sphere. The study shows further how even just a brief discussion with parents coupled with a guidebook to support parenting is associated with parental reports on favourable changes in children's well being. This reflects depressed parents' immanent need and openness for support, when it is available as part of their own treatment.

The study provides evidence base for including preventive child mental health interventions in the treatment protocols for adult depressed patients. There are methods available, practitioners can be trained to do them, and the results are favourable. Our study gives support to the countrywide EC&F Programme in Finland [36] in its efforts to make a system change in psychiatric services for adults to include child mental health promotion and disorder prevention.

We hope that our findings encourage decision makers and clinicians also beyond Finland to heed to the needs of mentally ill parents and their children. This call for action has recently been expressed in NRC and IOM report [25] and in the editorial of American Journal of Psychiatry [START_REF] Reiss | Transmission and treatment of depression[END_REF]. Norway and Sweden have joined Finland in legislating mental health promotion and disorder prevention for dependent children in health services for adults from the beginning of 2010. In Finland, the preventive and promotive work has extended to psychiatric patients with other than depression diagnosis, to parents with alcohol and drug abuse problems, to parents with severe somatic illness especially in cancer clinics, and to families with child protection needs. The training of the FTI has been condensed to 10-12 days.

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Training

  Clinicians working in mental health centres were trained to do the interventions. Training for the LT was three hours. Training for the FTI lasted about two years with 17 training days a year. The training included supervision of the trainees' cases as well as implementation issues.

  minutes. Sample The initial sample consisted of 119 families (60 LT, 59 FTI). Six families (3 LT, 3 FTI) withdrew from the study before baseline assessment. Both the baseline evaluation and the interventions were completed by 109 families (56 LT, 53 FTI). The final sample (with the main outcome measures) consisted of 53 and 53 families at baseline , 43 and 35 families at four months , and 40 and 39 families at 10 months and 44 and 40 families at 18 months in the LT and FTI, respectively (Figure

Figure 1 .

 1 Figure 1. Participant flow chart showing numbers of families randomly assigned.

  SD) a) covariated for the patient's baseline BDI and its change over BL vs 4 mo, N=98 b) covariated for the patient's baseline BDI and its change over BL vs 10 mo, N=106 c) covariated for the patient's baseline BDI and its change over BL vs 18 mo, N=100 d) covariated for the patient's baseline BDI and its change over time, N=107

Figure 2 .

 2 Figure 2. Graphical representations of the change in children's emotional symptoms and anxiety as well as prosocial behaviour in the FTI and LT interventions.

Table 1 .

 1 Demographic and diagnostic data of the participating families Mother was considered as the patient, if both parents had depression F Fischer's exact test

	LT	FTI
	N=53	N=53	p

Table 2 .

 2 Children's symptom scores according to parents in the two intervention groups at Baseline (BL), 4 month, 10 month and eighteen months follow-ups.

		BL		4 mo		10 mo		18 mo		BL vs 4 mo (a	BL vs 10 mo (b BL vs 18 mo (c	MIXED (d
											time*		time*		time*	time*
		LT	FTI	LT	FTI	LT	FTI	LT	FTI	time	group time	group time	group time	group
		mean	mean	mean	mean	mean	mean	mean	mean
		(SD)*	(SD)*	(SD)*	(SD)*	(SD)*	(SD)*	(SD)*	(SD)* p	p	p	p	p	p	p	p
	Emotional symptoms	(2.08) 2.18	(2.03) 2.46	(2.16) 2.26	(1.46) 1.53	(2.17) 1.85	(1.82) 1.88	(1.77) 1.73	(1.84) 1.77	0.196 0.012 0.009 0.430 0.005 0.478 0.036 0.040
	Hyperactivity 2.54	2.75	2.76	2.53	2.17	2.33	2.49	2.42	0.808 0.201 0.470 0.442 0.051 0.445 0.072 0.884
		(2.13)	(2.44)	(2.30)	(2.19)	(2.00)	(2.27)	(2.57)	(2.09)
	Conduct problems	(1.41) 1.93	(1.71) 2.29	(1.69) 1.80	(1.50) 2.04	(1.62) 1.83	(1.70) 2.12	(1.38) 1.58	(1.97) 2.00	0.019 0.189 0.515 0.142 0.105 0.216 0.608 0.442
	Peer problems	(1.95) 1.91	(1.82) 1.87	(1.55) 1.73	(1.37) 1.65	(1.98) 2.17	(1.69) 1.67	(2.06) 2.06	(1.61) 1.58	0.988 0.515 0.763 0.163 0.699 0.429 0.176 0.425
	Total symptoms	(5.52) 8.56	(5.87) 9.37	(5.61) 8.55	(4.32) 7.75	(5.99) 8.02	(5.45) 8.00	(5.97) 7.85	(5.32) 7.76	0.158 0.015 0.144 0.094 0.016 0.181 0.252 0.259
	Prosocial behaviour	(2.22) 6.86	(2.41) 6.14	(2.02) 6.90	(1.77) 7.06	(2.25) 6.79	(2.45) 6.87	(2.18) 7.79	(2.00) 7.75	0.153 0.021 0.173 0.024 <0.001 0.084 <0.001 0.157
	Anxiety	1.29	1.71			1.00	1.47	1.06	1.18	NA	NA	0.034 0.997 0.034 0.183 0.003 0.230
		(1.53)	(1.56) NA	NA	(1.50)	(1.66)	(1.43)	(1.58)

* crude mean and standard deviation (

Acknowledgements: We would like to thank all family members, clinics and clinicians who participated in the trial and made it possible. The study was funded by Finnish Academy Grants 77553; 215242; 209610 (TERTTU); 204337. KELA Dno 5/26/2006. Financial disclosure: The authors have no financial relationships to disclose.


W P M Th

C F M Mali

P C A Buckens

D E Jacobs

Y Grobbee

Graaf

MD Martijn J A Gondrie
email: m.gondrie@umcutrecht.nl

; W P M Th

MD, PhD Mali

MD ; C F M Buckens

MD, PhD ; P C A Jacobs

MD, PhD ; D E Grobbee

MD, PhD ; Y Van Der Graaf

Van Kuijk

Antonius St

Antonius

Milliampere Seconds

The PROgnostic Value of unrequested Information in Diagnostic Imaging

Keywords:

  L'archive ouverte pluridisciplinaire

Introduction

In this article the rationale and methods of the PROgnostic Value of unrequested Information in Diagnostic Imaging' (PROVIDI) study are presented. It was designed to investigate the growing amount of unrequested information, identified on diagnostic radiological examinations. PROVIDI's relatively large study sample and its innovative use of a case-cohort design place it in an ideal position to address some of the more challenging issues pertaining to unrequested radiological findings.

Rationale

Advances in radiological imaging techniques have led to scans of increasingly high resolution and contrast being deployed ever more widely, with the Computed Tomography (CT) 1 and Magnetic Resonance Imaging (MRI) 2 modalities leading the way. CT in particular is being deployed for a growing number of clinical indications and over the last decade alone CT image quality has evolved tremendously from single-section helical CT to the greater spatial and temporal resolution offered by multi-detector row CT (MDCT). 4-, 8-and 16-slice scanners are now widely in use, 64-and 256-slice scanners are being introduced into routine clinical practice whilst 320-slice scanners are in late phases of testing [START_REF] Silverman | Investigation of lung nodule detectability in low-dose 320-slice computed tomography[END_REF] .

The increasingly widespread use of higher quality CT in routine diagnostic clinical care is causing a corresponding increase in the numbers of unrequested findings being detected, which previously would have gone unnoticed; characterized as unrequested information which is unrelated to the initial scanning indication [START_REF] Jacobs | Prevalence of incidental findings in computed tomographic screening of the chest: a systematic review[END_REF][START_REF] Horton | Prevalence of significant noncardiac findings on electron-beam computed tomography coronary artery calcium screening examinations[END_REF] . As the referrals for routine scanning are typically highly targeted at investigating specific pathologies in specific organs, there is plenty of scope for unrequested findings that are not linked to these initial referrals. These referrals are typically the only additional clinical information that radiologists possess, adding to the uncertainty over how to handle unrequested findings. Evidence from the literature indicates that, on the whole, a large number of unrequested findings are not addressed in routine clinical settings [START_REF] Munk | Frequency and follow-up of incidental findings on trauma computed tomography scans: experience at a level one trauma center[END_REF] , whilst others may be subject to aggressively defensive follow-up [START_REF] Iribarren | Incidental pulmonary nodules on cardiac computed tomography: prognosis and use[END_REF][START_REF] Xu | Smooth or attached solid indeterminate nodules detected at baseline CT screening in the NELSON study: cancer risk during 1 year of follow-up[END_REF] . Due to their uncertain clinical significance, such findings pose a novel challenge to radiologists and referring clinicians alike.

Contributing to this trend of increasingly detected unrequested information is the growing culture of medical litigation wherein radiological lawsuits pertaining to missed diagnoses and perceived failure to initiate follow-up investigations form a growing majority of the total [START_REF] Berlin | Malpractice and radiologists in Cook County, IL: trends in 20 years of litigation[END_REF] . This follow-up exposes patients to potential harm in the form of unnecessary radiation exposure, invasive procedures, the anxiety and stress associated with an uncertain disease-state, as well as financial cost [START_REF] Machaalany | Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography[END_REF] .

Additionally, to date the impact of emerging diagnostic findings, such as arterial calcium scores and volumetric analysis of lung nodules [START_REF] Van Klaveren | Management of lung nodules detected by volume CT scanning[END_REF] , are only partially understood and go largely unutilized in routine care. The fact that many potentially predictive findings, as unrequested detected findings, may be available in some form for free on routine scans makes the investigation of their implementation necessary. The potential for risk stratification and preventative treatment for a range of disorders spanning from cardiovascular disease to osteoporosis using unrequested imaging characteritics extracted from the hodgepodge of routine scanning equipment and protocols could be unlocked by demonstrating the prognostic utility of this approach.

The question of how best to adapt to the growing number of unrequested findings has engendered lively debate amongst radiologists, with opinions ranging from advocacy of maximal pursuit for and follow-up of all available findings, to deliberately ignoring anatomical regions and findings beyond the mandates of the scan indication [START_REF] Budoff | Ethical issues related to lung nodules on cardiac CT[END_REF][START_REF] Kalra | Interpretation of incidental findings on cardiac CT angiography[END_REF][START_REF] Mulshine | Volume CT for diagnosis of nodules found in lung-cancer screening[END_REF][START_REF] Hlatky | The dilemma of incidental findings on cardiac computed tomography[END_REF] . This debate takes place in the context of the limited clinical information typically available to the radiologist and such discussions are a consequence of rapidly advancing techniques with attendant lack of knowledge of their implications. Debate will continue until follow-up studies are performed to investigate which unrequested scan findings are significant and which findings have no clinical impact. For these reasons, there is the urgent need of follow-up studies in routine radiologic settings; there have been but a few admirable attempts 10 at collecting follow-up data on patients with unrequested findings but virtually none investigating the prognostic endpoints. The work carried out in screening settings may not be representative for routine care settings due to for example different hazards for experiencing outcome events and concurrently, there is no basis for comparison between routine-care settings and the radiological prognostic research carried out so far in research settings using screening populations.

The PROVIDI study is the first study that aims to address these issues. It is designed as a longitudinal study, linking unrequested information detected on routine diagnostic Chest CT scans to major health outcomes via national health registries. In doing so we are able to identify those readily accessible unrequested findings that are prognostically relevant and sort them from findings that have little or no value to the patient (figure1). This may allow clinical radiologists to contribute more generally than before to patient care by more effectively utilizing the increasing amount of diagnostic information available, thereby increasing the efficiency of health care. .

Methods

Study Design

The PROVIDI study is designed as a multi-center retrospective case-cohort study. The cohort consists of subjects with routinely made chest CT scans obtained from eight participating hospitals (Elkerliek Hospital (Elkerliek), Gelre Hospitals(Gelre), St. Antonius Hospital(Antonius), Academic Medical Center Amsterdam(AMC), VU University Medical Center(VUMC), University Medical Center Groningen(UMCG), Academic Hospital Maastricht(AZM), and University Medical Center Utrecht(UMCU)), of which the latter five are tertiary referral centers. A case-cohort design offers significant gains in efficiency over a standard cohort study [START_REF] Prentice | A case-cohort design for epidemiologic cohort studies and disease prevention trials[END_REF] , at the cost of increased complexity in data analysis and the addition of a theoretical layer of assumptions about the uniformity of the cohort.

The crucial difference from a normal cohort study is that a random control sample of the cohort is selected at baseline to represent the cohort, making it unnecessary to analyse the whole cohort. Each (cluster of) unrequested finding of interest can then be studied in such an individual sub study that combines the cases that suffered outcome(s) relevant to that finding during follow-up with a new random sample of controls that did not. The control group is to be randomly sampled so that the group is twice as large as the case group for the individual sub study. This permits the use of the PROVIDI cohort in the investigation of the prognostic value of a range of unrelated unrequested findings, as well giving researchers the freedom to pursue unforeseen candidate findings as they emerge. Valid absolute risks, which are indispensable to prognostic research, can be readily calculated.

It was not possible to evaluate the extent of clinical follow-up undergone by patients as a result of unrequested findings with this study design. We did not consider this to be a serious limitation as this is rare in practice [START_REF] Munk | Frequency and follow-up of incidental findings on trauma computed tomography scans: experience at a level one trauma center[END_REF] and at any rate, it would cause an underestimation of the prognostic effect (as those receiving preventative therapies are probably less likely to experience the outcome of interest).

The PROVIDI study was approved by the Medical Ethics Committee of the University Medical Center Utrecht. The need for written informed consent was waived for all patients due to the retrospective design of this study. A privacy protocol was implemented to ensure that no patient information would be visible whilst reading CT scans and no additional information could be obtained from patient's medical records and no patient would be contacted as a result of this study.

Study subjects

All patients aged 40 years and older who were referred to one of the participating hospitals with an indication for a chest MDCT between January 2002 and the end of December 2005 were evaluated for inclusion in the PROVIDI study (N=23.443). Patients with suspected primary lung cancer (including mesothelioma) or distant metastatic disease from other types of cancer (excluding haematological malignancies), 9.077 cases in all, were excluded, on the basis that it is highly unlikely that detection of unrequested imaging findings will alter clinical decision making in patients with such a poor prognosis. This selection was first fully evaluated in a pilot study (table 1, textbox, pilot study).

Consequently, the PROVIDI cohort consists of 14.366 patients, and an equal number of chest CT's. In cases where patients underwent more than one chest CT examination, only the first CT scan of the series was used for analysis. The chest CT's were obtained with 2-, 4-, 8-, 16-, 32-or 64-slice scanners of different vendors. All types of chest CT protocols, including contrast and non-contrast scans, were eligible for the PROVIDI study. The CT scans were initially assessed by local hospital radiologists, consistent with routine practice. Subsequently, anonymous copies of all images were stored on disk and transferred to the University Medical Center Utrecht. Patient characteristics and information on type of CT protocol used, including section thickness, tube voltage (kVp), tube load (mAs), and the use of a contrast agent, was abstracted from CT reports by a research physician, who also assessed the CT indication from the CT reports.

Image findings

The specific candidate image findings will differ for each individual study investigating different specific groupings of disease entities and will be selected for their potential prognostic value, as suggested by the available literature and expert opinions from experienced radiologists as well as other clinical specialists and epidemiologists. CT scans will be reviewed, blinded for general scan parameters, CT indication and the outcome status, at a computer workstation, by trained research physicians and supervised by an experienced chest radiologist. Images are to be viewed at standard lung, soft tissue, and bone settings, which are also readily available to radiologists in clinical practice.

Reproducibility of image findings will be evaluated and must be sufficient. Some examples of the types of candidate unrequested scan findings are listed in figure 2.

Endpoints

All endpoints of the PROVIDI study are listed in table 2. Ideal endpoints would be prevalent diseases in with a major clinical impact and can be treated preventively when diagnosed at an early stage. The endpoints were ascertained through linkage with the National Death Registry and the National Registry of Hospital Discharge Diagnoses for the period January 2002-December 2006. Research showed that the quality of these databases was acceptable [START_REF] Paas | Research on the validity of the LMR[END_REF][START_REF] Mackenbach | Certification and coding of two underlying causes of death in The Netherlands and other countries of the European Community[END_REF] . Patients were identified through a combination of a patient's date of birth, sex, and zip code, using a validated probabilistic method [START_REF] Paas | Research on the validity of the LMR[END_REF][START_REF] Bruin | Record linkage of hospital discharge register with population register: experiences at Statistics Netherlands[END_REF][START_REF] Reitsma | Possibilities for anonymous follow-up studies of patients in Dutch national medical registrations using the Municipal Population Register: a pilot study[END_REF] . In these databases, cause of death and the occasion of hospitalization are coded according to the International Classification of Disease, 9 th 21 and 10 th revision 22 In an initial linkage, performed at a mean followup of 17 months, a total 5.243 out of the 14.366 patient cohort experienced a valid endpoint (table2). Note that this initial overview gives only a global indication of the numbers (here death prevailed over admission) and will be updated for each sub study to be performed.

Evaluation of data

PROVIDI will consist of a series of studies investigating potentially predictive scan findings for specific groupings of disease entities (e.g. cardiovascular diseases). The study populations of these studies will consist of the patients that suffered the relevant disease(s) under study during the followup period, as well as a random sample of patients from the PROVIDI cohort (the sub-cohort). In each of these studies, patients with a reported CT indication directly related to the disease under study will be excluded, to ensure that the image findings under study can legitimately be defined as unrequested information, in keeping with the stated goals of PROVIDI.(table 3, textbox, example study population)

Figure 3 shows the flowchart of the PROVIDI design.

We intend to analyse the scan findings both univariately and multivariately under study using Cox proportional hazard models, the most widely used statistical model for survival outcome in medical research. In multivariate analysis infromation readily available to radiologists in routine care(age, gender, CT indication, scanning parameters and quality) will be incorporated. The hazard ratios and standard errors will be modified based on robust variance estimates. These adaptations are to be carried out using the method according to Prentice, in which all sub cohort members are equally weighted [START_REF] Prentice | A case-cohort design for epidemiologic cohort studies and disease prevention trials[END_REF] . Cases outside the sub cohort are not to be weighted before failure and at failure receive the same weight as members of the sub cohort This method has been shown to resemble most closely estimates from a full-cohort analysis [START_REF] Onland-Moret | Analysis of case-cohort data: a comparison of different methods[END_REF] , without requiring a full analysis.

Discussion

Investigating which image findings have prognostic value andperhaps more importantly -which findings do not, is the first step in a process that has great potential to improve clinical care. The findings of the PROVIDI study will be of great interest to radiologists, but also to referring physicians.

The unique longitudinal study design, that places outcomes that matter to patients at its heart, gives this study the potential to meaningfully quantify the uncertainties facing diagnosticians and protect patients from potential over-diagnosis and over treatment. In the face of an absence of research investigating patient outcomes in routine-care, non-screening settings, radiologists are regularly responding defensively with exhaustive follow-up. An illustrative example is that of lung nodules, which are routinely detected on thoracic CT scans of all types, and which are frequently followed-up, despite evidence pointing to a low yield of significant pathology, at least in research/ screening settings [START_REF] Iribarren | Incidental pulmonary nodules on cardiac computed tomography: prognosis and use[END_REF][START_REF] Xu | Smooth or attached solid indeterminate nodules detected at baseline CT screening in the NELSON study: cancer risk during 1 year of follow-up[END_REF] .

By drawing on non-screening, routine clinical data it may both alleviate the dearth in radiological routine-care outcome data and serve as a basis for comparison with previous evidence from screening populations. A consequence of this study design is that patients at risk for a certain outcome will be identified using these models by radiologists while they may be already identified as such by other specialists, resulting in an overestimation of the clinical impact of certain incidental findings. Such double risk stratification would not have any negative effect for patients: the high risk indication from a radiologist is obtained freely(without additional radioation exposure) and can serve as a stimulus to verify whether optimal treatment has been initiated. In some cases this treatment is already optimal and a referring clinician can then ignore the 'red flag' if not, the referring specialist can consider additional investigations or start preventative treatment.

Translating the insights that might be gained from this study into clinical practice remains beyond the scope and means of PROVIDI itself but constitutes a crucial next step. Future clinical studies prospectively evaluating the efficacy and feasibility of implementing changes to clinical practice based upon PROVIDI's findings could demonstrate the benefit of fully utilizing the potential of modern scanning technology. in the study design, data collection, analysis and interpretation, the writing of the report, or the decision to submit the paper for publication.

Table 1, textbox, explanation of pilot study

Pilot Study

A pilot study was conducted to investigate if the indication categories could be used to identify patients with a very bad prognosis a priori.

For this pilot study, all patients, older than 40 years and undergoing thoracic CT at the University Medical Center Utrecht and Academic Hospital Maastricht were included. Information about mortality was gathered through linkage with the National Death Registry after complete follow-up. A comparison was made between patients who deceased within six months of follow-up and patients who deceased after six months of follow-up.

Patients with indication categories 'Suspected primary lung cancer (including mesothelioma)' and 'distant metastatic disease from other types of cancer (excluding haematological malignancies)' had an average mortality rate within 6 months of 33.9%. This was much higher compared to the mortality rate for the other indication categories (mean 10.4%, p<0.001).

We concluded that the indication categories can discriminate well between patients' prognoses and could be used to exclude patients with a bad prognosis a priori.

Table 3, textbox, example study population

Example study population

The study population for a study investigating the prognostic value of unrequested detected image findings that may be predictive for cardiovascular disease will consist of all patients that experienced a cardiovascular event during follow-up plus a random sample from the PROVIDI cohort. Patients with a cardiovascular indication for obtaining the chest CT are excluded, making sure that the image findings under study are truly unrequested.

Figure 1 :Figure 2 :

 12 Figure 1: Objective of the PROVIDI-study

Figure 3 :

 3 Figure 3: Flowchart of PROVIDI study. ? indicates that these numbers differ per conducted study

Acknowledgements / funding sources

We acknowledge the help with data collection and administrative support by Cees Haaring (UMCU), Karin Flobbe (AZM), Mirjam Borg (VUMC), Pascal Verzijl (Antonius), Jan Wolfers (AMC), Peter van Ooijen (UMCG), Willie Donkers (Elkerliek), and Robert Dragt (Gelre).

Funding: This study was funded by a program grant from the Netherlands Organization for Scientific Research-Medical Sciences (NWO-MW) grant 40-00812-98-07-005). The funders had no involvement