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1.  Missing Data Approaches in eHealth Research: Simulation Study and a Tutorial for Nonmathematically Inclined Researchers 
Missing data is a common nuisance in eHealth research: it is hard to prevent and may invalidate research findings.
In this paper several statistical approaches to data “missingness” are discussed and tested in a simulation study. Basic approaches (complete case analysis, mean imputation, and last observation carried forward) and advanced methods (expectation maximization, regression imputation, and multiple imputation) are included in this analysis, and strengths and weaknesses are discussed.
The dataset used for the simulation was obtained from a prospective cohort study following participants in an online self-help program for problem drinkers. It contained 124 nonnormally distributed endpoints, that is, daily alcohol consumption counts of the study respondents. Missingness at random (MAR) was induced in a selected variable for 50% of the cases. Validity, reliability, and coverage of the estimates obtained using the different imputation methods were calculated by performing a bootstrapping simulation study.
In the performed simulation study, the use of multiple imputation techniques led to accurate results. Differences were found between the 4 tested multiple imputation programs: NORM, MICE, Amelia II, and SPSS MI. Among the tested approaches, Amelia II outperformed the others, led to the smallest deviation from the reference value (Cohen’s d = 0.06), and had the largest coverage percentage of the reference confidence interval (96%).
The use of multiple imputation improves the validity of the results when analyzing datasets with missing observations. Some of the often-used approaches (LOCF, complete cases analysis) did not perform well, and, hence, we recommend not using these. Accumulating support for the analysis of multiple imputed datasets is seen in more recent versions of some of the widely used statistical software programs making the use of multiple imputation more readily available to less mathematically inclined researchers.
PMCID: PMC3057309  PMID: 21169167
Missing data; multiple imputation; Internet; methodology
2.  Variability in the prevalence of adult ADHD in treatment seeking substance use disorder patients: Results from an international multi-center study exploring DSM-IV and DSM-5 criteria☆☆ 
Drug and alcohol dependence  2013;134:158-166.
Available studies vary in their estimated prevalence of attention deficit/hyperactivity disorder (ADHD) in substance use disorder (SUD) patients, ranging from 2 to 83%. A better understanding of the possible reasons for this variability and the effect of the change from DSM-IV to DSM-5 is needed.
A two stage international multi-center, cross-sectional study in 10 countries, among patients form inpatient and outpatient addiction treatment centers for alcohol and/or drug use disorder patients. A total of 3558 treatment seeking SUD patients were screened for adult ADHD. A subsample of 1276 subjects, both screen positive and screen negative patients, participated in a structured diagnostic interview.
Prevalence of DSM-IV and DSM-5 adult ADHD varied for DSM-IV from 5.4% (CI 95%: 2.4–8.3) for Hungary to 31.3% (CI 95%:25.2–37.5) for Norway and for DSM-5 from 7.6% (CI 95%: 4.1–11.1) for Hungary to 32.6% (CI 95%: 26.4–38.8) for Norway. Using the same assessment procedures in all countries and centers resulted in substantial reduction of the variability in the prevalence of adult ADHD reported in previous studies among SUD patients (2–83%→ 5.4–31.3%). The remaining variability was partly explained by primary substance of abuse and by country (Nordic versus non-Nordic countries). Prevalence estimates for DSM-5 were slightly higher than for DSM-IV.
Given the generally high prevalence of adult ADHD, all treatment seeking SUD patients should be screened and, after a confirmed diagnosis, treated for ADHD since the literature indicates poor prognoses of SUD in treatment seeking SUD patients with ADHD.
PMCID: PMC4133781  PMID: 24156882
Prevalence; Substance use disorder; Attention deficit hyperactivity disorder; DSM-5; Adults
3.  Psychiatric comorbidity in treatment-seeking substance use disorder patients with and without attention deficit hyperactivity disorder: results of the IASP study 
Addiction (Abingdon, England)  2013;109(2):262-272.
To determine comorbidity patterns in treatment-seeking substance use disorder (SUD) patients with and without adult attention deficit hyperactivity disorder (ADHD), with an emphasis on subgroups defined by ADHD subtype, taking into account differences related to gender and primary substance of abuse.
Data were obtained from the cross-sectional International ADHD in Substance use disorder Prevalence (IASP) study.
Forty-seven centres of SUD treatment in 10 countries.
A total of 1205 treatment-seeking SUD patients.
Structured diagnostic assessments were used for all disorders: presence of ADHD was assessed with the Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID), the presence of antisocial personality disorder (ASPD), major depression (MD) and (hypo)manic episode (HME) was assessed with the Mini International Neuropsychiatric Interview-Plus (MINI Plus), and the presence of borderline personality disorder (BPD) was assessed with the Structured Clinical Interview for DSM-IV Axis II (SCID II).
The prevalence of DSM-IV adult ADHD in this SUD sample was 13.9%. ASPD [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.8–4.2], BPD (OR = 7.0, 95% CI = 3.1–15.6 for alcohol; OR = 3.4, 95% CI = 1.8–6.4 for drugs), MD in patients with alcohol as primary substance of abuse (OR = 4.1, 95% CI = 2.1–7.8) and HME (OR = 4.3, 95% CI = 2.1–8.7) were all more prevalent in ADHD+ compared with ADHD− patients (P < 0.001). These results also indicate increased levels of BPD and MD for alcohol compared with drugs as primary substance of abuse. Comorbidity patterns differed between ADHD subtypes with increased MD in the inattentive and combined subtype (P < 0.01), increased HME and ASPD in the hyperactive/impulsive (P < 0.01) and combined subtypes (P < 0.001) and increased BPD in all subtypes (P < 0.001) compared with SUD patients without ADHD. Seventy-five per cent of ADHD patients had at least one additional comorbid disorder compared with 37% of SUD patients without ADHD.
Treatment-seeking substance use disorder patients with attention deficit hyperactivity disorder are at a very high risk for additional externalizing disorders.
PMCID: PMC4112562  PMID: 24118292
ADHD; antisocial personality disorder; bipolar disorder; borderline personality disorder; comorbidity; depression; substance use disorder
4.  Validity of the Adult ADHD Self-Report Scale (ASRS) as a screener for adult ADHD in treatment seeking substance use disorder patients 
Drug and alcohol dependence  2013;132(3):587-596.
To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed.
To test the performance of the Adult ADHD Self-Report Scale V1.1(ASRS) for adult ADHD in an international sample of treatment seeking SUD patients for DSM-IV-TR; for the proposed DSM-5 criteria; in different subpopulations, at intake and 1–2 weeks after intake; using different scoring algorithms; and different externalizing disorders as external criterion (including adult ADHD, bipolar disorder, antisocial and borderline personality disorder).
In 1138 treatment seeking SUD subjects, ASRS performance was determined using diagnoses based on Conner’s Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as gold standard.
The prevalence of adult ADHD was 13.0% (95% CI: 11.0–15.0%). The overall positive predictive value (PPV) of the ASRS was 0.26 (95% CI: 0.22–0.30), the negative predictive value (NPV) was 0.97 (95% CI: 0.96–0.98). The sensitivity (0.84, 95% CI: 0.76–0.88) and specificity (0.66, 95% CI: 0.63–0.69) measured at admission were similar to the sensitivity (0.88,95% CI: 0.83–0.93) and specificity (0.67,95% CI: 0.64–0.70) measured 2 weeks after admission. Sensitivity was similar, but specificity was significantly better in patients with alcohol compared to (illicit) drugs as the primary substance of abuse (0.76 vs. 0.56). ASRS was not a good screener for externalizing disorders other than ADHD.
The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population.
PMCID: PMC4083506  PMID: 23660242
ADHD; Substance use disorders; Prevalence; Attention/deficit hyperactivity disorder; Validity; ASRS; Addiction; Psychiatry
5.  Perceived Impeding Factors for Return-to-Work after Long-Term Sickness Absence Due to Major Depressive Disorder: A Concept Mapping Approach 
PLoS ONE  2014;9(1):e85038.
The purpose of the present study was to explore various stakeholder perspectives regarding factors that impede return-to-work (RTW) after long-term sickness absence related to major depressive disorder (MDD).
Concept mapping was used to explore employees', supervisors' and occupational physicians' perspectives on these impeding factors.
Nine perceived themes, grouped in three meta-clusters were found that might impede RTW: Person, (personality / coping problems, symptoms of depression and comorbid (health) problems, employee feels misunderstood, and resuming work too soon), Work (troublesome work situation, too little support at work, and too little guidance at work) and Healthcare (insufficient mental healthcare and insufficient care from occupational physician). All stakeholders regarded personality/coping problems and symptoms of depression as the most important impeding theme. In addition, supervisors emphasized the importance of mental healthcare underestimating the importance of the work environment, while occupational physicians stressed the importance of the lack of safety and support in the work environment.
In addition to the reduction of symptoms, more attention is needed on coping with depressive symptoms and personality problems in the work environment support in the work environment and for RTW in mental healthcare, to prevent long term sickness absence.
PMCID: PMC3893138  PMID: 24454786
6.  Ala54Thr Fatty Acid-Binding Protein 2 (FABP2) Polymorphism in Recurrent Depression: Associations with Fatty Acid Concentrations and Waist Circumference 
PLoS ONE  2013;8(12):e82980.
Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid–binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference.
We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls.
FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2ω6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2ω6, and (II) different from controls.
Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment.
PMCID: PMC3858331  PMID: 24340071
7.  Investigating the efficacy of integrated cognitive behavioral therapy for adult treatment seeking substance use disorder patients with comorbid ADHD: study protocol of a randomized controlled trial 
BMC Psychiatry  2013;13:132.
Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders (SUD). The combination of ADHD and SUD is associated with a negative prognosis of both SUD and ADHD. Pharmacological treatments of comorbid ADHD in adult patients with SUD have not been very successful. Recent studies show positive effects of cognitive behavioral therapy (CBT) in ADHD patients without SUD, but CBT has not been studied in ADHD patients with comorbid SUD.
This paper presents the protocol of a randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in SUD patients with a comorbid diagnosis of ADHD. The experimental group receives 15 CBT sessions directed at symptom reduction of SUD as well as ADHD. The control group receives treatment as usual, i.e. 10 CBT sessions directed at symptom reduction of SUD only. The primary outcome is the level of self-reported ADHD symptoms. Secondary outcomes include measures of substance use, depression and anxiety, quality of life, health care consumption and neuropsychological functions.
This is the first randomized controlled trial to test the efficacy of an integrated CBT protocol for adult SUD patients with a comorbid diagnosis of ADHD. The rationale for the trial, the design, and the strengths and limitations of the study are discussed.
Trial registration
This trial is registered in as NCT01431235.
PMCID: PMC3659028  PMID: 23663651
ADHD; SUD; Cognitive behavioral therapy; Adult; Integrated treatment
8.  Can a One-Item Mood Scale Do the Trick? Predicting Relapse over 5.5-Years in Recurrent Depression 
PLoS ONE  2012;7(10):e46796.
To examine whether a simple Visual Analogue Mood Scale (VAMS) is able to predict time to relapse over 5.5-years.
Methodology/Principal Findings
187 remitted recurrently depressed out-patients were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the 17-item Hamilton Depression rating scale (HAM-D) to verify remission status (HAM-D <10). All patients rated their current mood with the help of a Visual Analogue Mood Scale (VAMS) at baseline and at a follow-up assessment three months later. Relapse over 5.5-years was assessed by the SCID-I. Cox regression revealed that both the VAMS at baseline and three months later significantly predicted time to relapse over 5.5-years. Baseline VAMS even predicted time to relapse when the number of previous depressive episodes and HAM-D scores were controlled for. The baseline VAMS explained 6.3% of variance in time to relapse, comparable to the HAM-D interview.
Sad mood after remission appears to play a pivotal role in the course of depression. Since a simple VAMS predicted time to relapse, the VAMS might be an easy and time-effective way to monitor mood and risk of early relapse, and offers possibilities for daily monitoring using e-mail and SMS.
Trial Registration
International Standard Randomized Controlled Trial Register Identifier: ISRCTN68246470.
PMCID: PMC3463530  PMID: 23056456
9.  Towards a New Definition of Return-to-Work Outcomes in Common Mental Disorders from a Multi-Stakeholder Perspective 
PLoS ONE  2012;7(6):e39947.
To examine the perspectives of key stakeholders involved in the return-to-work (RTW) process regarding the definition of successful RTW outcome after sickness absence related to common mental disorders (CMD’s).
A mixed-method design was used: First, we used qualitative methods (focus groups, interviews) to identify a broad range of criteria important for the definition of successful RTW (N = 57). Criteria were grouped into content-related clusters. Second, we used a quantitative approach (online questionnaire) to identify, among a larger stakeholder sample (N = 178), the clusters and criteria most important for successful RTW.
A total of 11 clusters, consisting of 52 unique criteria, were identified. In defining successful RTW, supervisors and occupational physicians regarded “Sustainability” and “At-work functioning” most important, while employees regarded “Sustainability,” “Job satisfaction,” “Work-home balance,” and “Mental Functioning” most important. Despite agreement on the importance of certain criteria, considerable differences among stakeholders were observed.
Key stakeholders vary in the aspects and criteria they regard as important when defining successful RTW after CMD-related sickness absence. Current definitions of RTW outcomes used in scientific research may not accurately reflect these key stakeholder perspectives. Future studies should be more aware of the perspective from which they aim to evaluate the effectiveness of a RTW intervention, and define their RTW outcomes accordingly.
PMCID: PMC3386986  PMID: 22768180
10.  Statistical Methodological Issues in Handling of Fatty Acid Data: Percentage or Concentration, Imputation and Indices 
Lipids  2012;47(5):541-547.
Basic aspects in the handling of fatty acid-data have remained largely underexposed. Of these, we aimed to address three statistical methodological issues, by quantitatively exemplifying their imminent confounding impact on analytical outcomes: (1) presenting results as relative percentages or absolute concentrations, (2) handling of missing/non-detectable values, and (3) using structural indices for data-reduction. Therefore, we reanalyzed an example dataset containing erythrocyte fatty acid-concentrations of 137 recurrently depressed patients and 73 controls. First, correlations between data presented as percentages and concentrations varied for different fatty acids, depending on their correlation with the total fatty acid-concentration. Second, multiple imputation of non-detects resulted in differences in significance compared to zero-substitution or omission of non-detects. Third, patients’ chain length-, unsaturation-, and peroxidation-indices were significantly lower compared to controls, which corresponded with patterns interpreted from individual fatty acid tests. In conclusion, results from our example dataset show that statistical methodological choices can have a significant influence on outcomes of fatty acid analysis, which emphasizes the relevance of: (1) hypothesis-based fatty acid-presentation (percentages or concentrations), (2) multiple imputation, preventing bias introduced by non-detects; and (3) the possibility of using (structural) indices, to delineate fatty acid-patterns thereby preventing multiple testing.
PMCID: PMC3334488  PMID: 22446846
Multiple imputation; Non-detectable values; Undetectable; Peroxidation index (PI); Unsaturation index (UI); Chain length index; Eicosapentaenoic acid (EPA); Docosahexaenoic acid (DHA); Polyunsaturated fatty acids (PUFA); Recurrent major depressive disorder; Life Sciences; Nutrition; Medicinal Chemistry; Medical Biochemistry; Lipidology; Neurochemistry; Microbial Genetics and Genomics
11.  Decision making as a predictor of first ecstasy use: a prospective study 
Psychopharmacology  2008;203(3):519-527.
Ecstasy (±3,4-methylenedioxymethamphetamine) is a widely used recreational drug that may damage the serotonin system and may entail neuropsychological dysfunctions. Few studies investigated predictors for ecstasy use. Self-reported impulsivity does not predict the initiation of ecstasy use; the question is if neuropsychological indicators of impulsivity can predict first ecstasy use.
This study tested the hypothesis that a neuropsychological indicator of impulsivity predicts initiation of ecstasy use.
Materials and methods
Decision-making strategy and decision-making reaction times were examined with the Iowa Gambling Task in 149 ecstasy-naive subjects. The performance of 59 subjects who initiated ecstasy use during a mean follow-up period of 18 months (range, 11–26) was compared with the performance of 90 subjects that remained ecstasy-naive.
Significant differences in decision-making strategy between female future ecstasy users and female persistent ecstasy-naive subjects were found. In addition, the gap between decision-making reaction time after advantageous choices and reaction time after disadvantageous choices was smaller in future ecstasy users than in persistent ecstasy-naives.
Decision-making strategy on a gambling task was predictive for future use of ecstasy in female subjects. Differences in decision-making time between future ecstasy users and persistent ecstasy-naives may point to lower punishment sensitivity or higher impulsivity in future ecstasy users. Because differences were small, the clinical relevance is questionable.
PMCID: PMC2761546  PMID: 19020868
Ecstasy; MDMA; Decision-making; Iowa Gambling Task; Neuropsychology
12.  Using the Autism-Spectrum Quotient to Discriminate Autism Spectrum Disorder from ADHD in Adult Patients With and Without Comorbid Substance Use Disorder 
It is unknown whether the Autism-spectrum quotient (AQ) can discriminate between Autism Spectrum Disorder (ASD) and Attention Deficit and Hyperactivity Disorder (ADHD) with or without comorbid Substance Use Disorder (SUD). ANOVA’s were used to analyse the mean AQ (sub)scores of 129 adults with ASD or ADHD. We applied receiver operating characteristic (ROC) computations to assess discriminant power. All but one of the mean AQ (sub)scores were significantly higher for adults with ASD compared to those with ADHD. The SUD status in general was not significantly associated with AQ (sub)scores. On the Social Skills subscale patients with ASD and comorbid SUD showed less impairment than those without SUD. The cut-off score 26 yielded 73% correct classifications. The clinical use of the AQ in differentiating between ASD and ADHD is limited.
PMCID: PMC2727364  PMID: 19396535
Autism spectrum disorder; ADHD; Substance use disorder; Autism-spectrum quotient
13.  Medication Adherence in Schizophrenia: Exploring Patients', Carers' and Professionals' Views 
Schizophrenia Bulletin  2006;32(4):786-794.
One of the major clinical problems in the treatment of people with schizophrenia is suboptimal medication adherence. Most research focusing on determinants of nonadherence use quantitative research methods. These studies have some important limitations in exploring the decision-making process of patients concerning medication. In this study we explore factors influencing medication adherence behavior in people with schizophrenia using concept mapping. Concept mapping is a structured qualitative method and was performed in 4 European countries. Participants were 27 patients with schizophrenia, 29 carers, and 28 professionals of patients with schizophrenia. Five clinically relevant themes were identified that affect adherence: medication efficacy, external factors (such as patient support and therapeutic alliance), insight, side effects, and attitudes toward medication. Importance ratings of these factors differed significantly between professionals and carers and patients. Professionals, carers, and patients do not have a shared understanding of which factors are important in patients' medication adherence behavior. Adherence may be positively influenced if professionals focus on the positive aspects of medication, on enhancing insight, and on fostering a positive therapeutic relationship with patients and carers.
PMCID: PMC2632275  PMID: 16887889
medication adherence; schizophrenia; concept mapping
14.  Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials 
BMJ : British Medical Journal  2003;327(7410):310.
Objective To determine whether supervised medical prescription of heroin can successfully treat addicts who do not sufficiently benefit from methadone maintenance treatment.
Design Two open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 549 heroin addicts.
Interventions Inhalable heroin (n = 375) or injectable heroin (n = 174) prescribed over 12 months. Heroin (maximum 1000 mg per day) plus methadone (maximum 150 mg per day) compared with methadone alone (maximum 150 mg per day). Psychosocial treatment was offered throughout.
Main outcome measures Dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.
Results Adherence was excellent with 12 month outcome data available for 94% of the randomised participants. With intention to treat analysis, 12 month treatment with heroin plus methadone was significantly more effective than treatment with methadone alone in the trial of inhalable heroin (response rate 49.7% v 26.9%; difference 22.8%, 95% confidence interval 11.0% to 34.6%) and in the trial of injectable heroin (55.5% v 31.2%; difference 24.3%, 9.6% to 39.0%). Discontinuation of the coprescribed heroin resulted in a rapid deterioration in 82% (94/115) of those who responded to the coprescribed heroin. The incidence of serious adverse events was similar across treatment conditions.
Conclusions Supervised coprescription of heroin is feasible, more effective, and probably as safe as methadone alone in reducing the many physical, mental, and social problems of treatment resistant heroin addicts.
PMCID: PMC169643  PMID: 12907482

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