Real-world data, such as administrative claims and electronic health records, are increasingly used for safety monitoring and to help guide regulatory decision-making. In these settings, it is important to document analytic decisions transparently and objectively to assess and ensure that analyses meet their intended goals.

The Causal Roadmap is an established framework that can guide and document analytic decisions through each step of the analytic pipeline, which will help investigators generate high-quality real-world evidence.

In this paper, we illustrate the utility of the Causal Roadmap using two case studies previously led by workgroups sponsored by the Sentinel Initiative – a program for actively monitoring the safety of regulated medical products. Each case example focuses on different aspects of the analytic pipeline for drug safety monitoring. The first case study shows how the Causal Roadmap encourages transparency, reproducibility, and objective decision-making for causal analyses. The second case study highlights how this framework can guide analytic decisions beyond inference on causal parameters, improving outcome ascertainment in clinical phenotyping.

These examples provide a structured framework for implementing the Causal Roadmap in safety surveillance and guide transparent, reproducible, and objective analysis.

The Trial Innovation Network (TIN) is a collaborative initiative within the National Center for Advancing Translational Science (NCATS) Clinical and Translational Science Awards (CTSA) Program. To improve and innovate the conduct of clinical trials, it is exploring the uses of gamification to better engage the trial workforce and improve the efficiencies of trial activities. The gamification structures described in this article are part of a TIN website gamification toolkit, available online to the clinical trial scientific community.

The game designers used existing electronic trial platforms to gamify the tasks required to meet trial start-up timelines to create friendly competitions. Key indicators and familiar metrics were mapped to scoreboards. Webinars were organized to share and applaud trial and game performance.

Game scores were significantly associated with an increase in achieving start-up milestones in activation, institutional review board (IRB) submission, and IRB approval times, indicating the probability of completing site activation faster by using games. Overall game enjoyment and feelings that the game did not apply too much pressure appeared to be an important moderator of performance in one trial but had little effect on performance in a second.

This retrospective examination of available data from gaming experiences may be a first-of-kind use in clinical trials. There are signals that gaming may accelerate performance and increase enjoyment during the start-up phase of a trial. Isolating the effect of gamification on trial outcomes will depend on a larger sampling from future trials, using well-defined, hypothesis-driven statistical analysis plans.

This study aimed to compare the effectiveness of pharmacological therapy with and without direct maxillary sinus saline irrigation for the management of chronic rhinosinusitis without polyps.

In this prospective randomised controlled trial, 39 non-operated patients were randomly assigned to be treated with direct maxillary sinus saline irrigation in conjunction with systemic antibiotics and topical sprays (n = 24) or with pharmacological therapy alone (n = 15). Endoscopy, Sino-Nasal Outcome Test and Lund–MacKay computed tomography scores were obtained before, six weeks after and one to two years after treatment.

Post-treatment Lund–Mackay computed tomography scores were significantly improved in both cohorts, with no inter-cohort difference identified. Post-treatment nasal endoscopy scores were significantly improved in the study group but were similar to those measured in the control group. The Sino-Nasal Outcome Test-20 results showed improvement in both cohorts, with no difference between treatment arms.

Maxillary sinus puncture and irrigation with saline, combined with pharmacological treatment improves endoscopic findings in patients with chronic rhinosinusitis without polyps, but has no beneficial effect on symptoms and imaging findings over conservative treatment alone.

There is evidence that, besides limbic brain structures, prefrontal and insular cortical activations and deactivations are involved in the pathophysiology of panic disorder.

Using fMRI, this study investigated BOLD response patterns to stimulation with individually selected panic-specific pictures in patients with panic disorder with agoraphobia (PDA) and healthy controls. Structures of interest were the prefrontal, cingulate, and insular cortex, and the amygdalo-hippocampal complex.

21 PDA subjects (12 female, 9 male) and 21 matched controls were investigated using a Siemens 3 T scanner. Before, PDA subjects gave ratings on 120 pictures showing characteristic panic/agoraphobia situations (PA). 20 pictures with the individually highest ratings were selected. 20 matching pictures showing aversive but not panic-specific stimuli (A) and 80 neutral pictures (N) from the International Affective Picture-System (IAPS) were chosen for each subject. Anxiety and depression ratings were recorded.

Group comparisons revealed a significantly greater BOLD response in PDA subjects than in controls in the insular cortices, left inferior frontal gyrus, dmPFC, the left hippocampal formation, and left caudatum (p < .005), when PA and N responses were compared. Group comparisons for stimulation with A compared to PA showed activation of similar brain regions in both groups but with different peak coordinates.

Results indicate specific activation patterns to panic-specific picture stimulation in PDA patients. Distinct peak coordinates between PA and A differ between groups. This might implicate that the brain circuits underlying processing of aversive stimuli might differ in their function in PDA patients compared to healthy subjects.

The authors presented their acitivities in prevention of mobbing, suiciality, pathological gambling, and antistigma programs aimed for the persons treated for combat PTSD.

Social dialogue is achieved through numerous outpatient activities that included systematic information and education, public discussions, conducted studies, public program promotions, performance presentations, koordination, and active engagement of various professionals (psychiatrists, psychologists, pedagogues, social workers, jurists, politicians, employees in civil service, associations and syndicate, employers, and volonteers).

Numerous public disscussions and professional gatherings have been held, professional and scientific studies have been conducted, programs have been presented in public through various media, web-pages have been created and brochures have been written. The created positve atmosphere leveled up the awarenes, what resulted in propositions for drawing up broader, national strategies, and some pending legal solutions.

Social dialoge is represented by all types of information exchange, conslutations, and discussions between social partners and government representatives about issues of common interest related to social or economic policy. In situations when some primalily social events partially participate in the genesis of psychological disorders, a psychiatrist may take part in the dialogue, pointing out the existance of the problem, defining the problem and offering professional solutions for prevention. In order to have a social dialogue it is necessary to have most extensive public support and understanding that only with joint endeavor of all citizens the problem may be, and must be, solved.

Parents of mentally ill patients are stigmatized by the disease of their ill family members, emotionally, socially and physically burdened. Authors are presenting a case report of a mother of 23 year old schizophrenic daughter, who started to attend support groups for families of mentally ill persons almost two years ago.

To investigate whether the joining to the association for families of mentally ill persons and regular attending to its programs (psycho educative lectures, support groups), would enable the mother of a patient with schizophrenia to re-establish her psychic balance by reducing high expressed emotion.

psychological test PIE (The profile index of emotions) three times during 18 months

PIE tests showed reduced high expressed emotions (fear, sorrow and anger). Mother turned from the depressive position in life and started to work positively with her daughter's illness, started to motivate other parents, and started to help them with her advice. She became one of the founders of the Society for Improvement of Mental Health and Quality of Life of Mentally Ill Persons and Their Families “Happy Family”, Croatia, where she is now a member of the Organizational board and is an accountant.

An active role in association for mentally ill persons re-established the psychic balance in this mother, changing her to a powerful, strong and competent person who not only can cope positively with her daughter's disease but also is able to help other parents in the same situation.

22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS.

Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions.

We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders.

These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS.

Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.

This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).

Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.

Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Civilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate.

The joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009.

There were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2–39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2–22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1–4.1], less so when previously deployed (OR 1.6, 95% CI 1.1–2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8–1.8). Adjustment for a differential ‘healthy warrior effect’ cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status.

Efforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk.

To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD).

Nationally or regionally representative epidemiological interviews were administered to 74 045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI).

45.7% of respondents with lifetime MDD (32.0–46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8–54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9–47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v. 46.0%; χ21 = 187.0, p < 0.001) and suicide ideation (19.5 v. 8.9%; χ21 = 71.6, p < 0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v. 45.4%; χ21 = 108.8, p < 0.001) than low/middle-income countries (30.3 v. 20.6%; χ21 = 11.7, p < 0.001).

Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6–74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v. causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.

Although variation in the long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods. However, it is not known whether these distinctions can be refined by added information about co-morbid conditions. The current report presents results on this question.

Data came from 8261 respondents with lifetime DSM-IV MDD in the World Health Organization (WHO) World Mental Health (WMH) Surveys. Outcomes included four retrospectively reported measures of persistence/severity of course (years in episode; years in chronic episodes; hospitalization for MDD; disability due to MDD). Machine learning methods (regression tree analysis; lasso, ridge and elastic net penalized regression) followed by k-means cluster analysis were used to augment previously detected subtypes with information about prior co-morbidity to predict these outcomes.

Predicted values were strongly correlated across outcomes. Cluster analysis of predicted values found three clusters with consistently high, intermediate or low values. The high-risk cluster (32.4% of cases) accounted for 56.6–72.9% of high persistence, high chronicity, hospitalization and disability. This high-risk cluster had both higher sensitivity and likelihood ratio positive (LR+; relative proportions of cases in the high-risk cluster versus other clusters having the adverse outcomes) than in a parallel analysis that excluded measures of co-morbidity as predictors.

Although the results using the retrospective data reported here suggest that useful MDD subtyping distinctions can be made with machine learning and clustering across multiple indicators of illness persistence/severity, replication with prospective data is needed to confirm this preliminary conclusion.

Cross-national population data from the WHO World Mental Health surveys are used to compare role attainments and role impairments associated with binge-eating disorder (BED) and bulimia nervosa (BN).

Community surveys assessed 23 000 adults across 12 countries for BED, BN and ten other DSM-IV mental disorders using the WHO Composite International Diagnostic Interview. Age-of-onset was assessed retrospectively. Ten physical disorders were assessed using standard conditions checklists. Analyses examined reciprocal time-lagged associations of eating disorders (EDs) with education, associations of early-onset (i.e., prior to completing education) EDs with subsequent adult role attainments and cross-sectional associations of current EDs with days of role impairment.

BED and BN predicted significantly increased education (females). Student status predicted increased risk of subsequent BED and BN (females). Early-onset BED predicted reduced odds of current (at time of interview) marriage (females) and reduced odds of current employment (males). Early-onset BN predicted increased odds of current work disability (females and males). Current BED and BN were both associated with significantly increased days of role impairment (females and males). Significant BED and BN effects on adult role attainments and impairments were explained by controls for comorbid disorders.

Effects of BED on role attainments and impairments are comparable with those of BN. The most plausible interpretation of the fact that these associations are explained by comorbid disorders is that causal effects of EDs are mediated through secondary disorders. Controlled treatment effectiveness studies are needed to trace out long-term effects of BED–BN on secondary disorders.

To determine the association between contact precautions and depression or anxiety as well as feelings of anger, sadness, worry, happiness, or confusion.

Prospective frequency-matched cohort study.

The University of Maryland Medical Center, a 662-bed tertiary care hospital in Baltimore, Maryland.

A total of 1,876 medical and surgical patients over the age of 18 years were approached; 528 patients were enrolled from January through November 2010, and 296 patients, frequency matched by hospital unit, completed follow-up on hospital day 3.

The primary outcome was Hospital Anxiety and Depression Scale (HADS) scores on hospital day 3, controlling for baseline HADS scores. Secondary moods were measured with visual analog mood scale diaries. Patients under contact precautions had baseline symptoms of depression 1.3 points higher (P < .01) and anxiety 0.8 points higher (P = .08) at hospital admission using HADS. Exposure to contact precautions was not associated with increased depression (P = .42) or anxiety (P = .25) on hospital day 3. On hospital day 3, patients under contact precautions were no more likely than unexposed patients to be angry (20% vs 20%; P = .99), sad (33% vs 38%; P = .45), worried (51% vs 46%; P = .41), happy (58% vs 67%; P = .14), or confused (23% vs 24%; P = .95).

Patients under contact precautions have more symptoms of depression and anxiety at hospital admission but do not appear to be more likely to develop depression, anxiety, or negative moods while under contact precautions. The use of contact precautions should not be restricted by the belief that contact precautions will produce more depression or anxiety.

Current trends in population aging affect both recipients and providers of informal family caregiving, as the pool of family caregivers is shrinking while demand is increasing. Epidemiological research has not yet examined the implications of these trends for burdens experienced by aging family caregivers.

Cross-sectional community surveys in 20 countries asked 13 892 respondents aged 50+ years about the objective (time, financial) and subjective (distress, embarrassment) burdens they experience in providing care to first-degree relatives with 12 broadly defined serious physical and mental conditions. Differential burden was examined by country income category, kinship status and type of condition.

Among the 26.9–42.5% respondents in high-, upper-middle-, and low-/lower-middle-income countries reporting serious relative health conditions, 35.7–42.5% reported burden. Of those, 25.2–29.0% spent time and 13.5–19.4% money, while 24.4–30.6% felt distress and 6.4–21.7% embarrassment. Mean caregiving hours per week in those giving any time were 16.6–23.6 (169.9–205.8 h/week per 100 people aged 50+ years). Burden in low-/lower-middle-income countries was 2- to 3-fold higher than in higher-income countries, with any financial burden averaging 14.3% of median family income in high-, 17.7% in upper-middle-, and 39.8% in low-/lower-middle-income countries. Higher burden was reported by women than men and for conditions of spouses and children than parents or siblings.

Uncompensated family caregiving is an important societal asset that offsets rising formal healthcare costs. However, the substantial burdens experienced by aging caregivers across multiple family health conditions and geographic regions threaten the continued integrity of their caregiving capacity. Initiatives supporting older family caregivers are consequently needed, especially in low-/lower-middle-income countries.