Search

BackgroundBipolar disorder (BD) conveys the highest risk of suicide of all mental disorders. We sought to externally validate a risk calculator (RC) of suicide attempts developed in youth with BD from the Course and Outcome of Bipolar Youth (COBY) study in an adult sample.MethodsA prospective cohort of adults with BD from the National Institute of Mental Health Collaborative Depression Study (CDS; N = 427; mean (+/- SD) age at intake (36 +/- 13 years)) was secondarily analyzed to validate the COBY RC for one-year risk of suicide attempts/deaths. Nine of the ten predictor variables from the COBY RC were available in the CDS and used: age, age of mood disorder onset, first and second (partial) degree family history of suicide, history of psychotic symptoms, substance use disorder, prior suicide attempt, socioeconomic status, and non-suicidal self-injury (prospectively, incompletely at baseline).ResultsOver a mean (SD) follow-up of 19 (10) years, 29 % of the CDS sample attempted suicide. The RC predicted suicide attempts/deaths over one-year follow-up with an area under the receiver operating characteristic curve (AUC) of 0.78 (95 % CI 0.75-0.80). The RC performed slightly better in those with a younger age of mood disorder onset.LimitationsClinical samples may limit generalizability; the RC does not assess more acute suicide risk.ConclusionsOne-year risk of suicide attempts/deaths can be predicted with acceptable accuracy in youth and adults with BD, comparable to commonly used RCs to predict cardiovascular risk. This RC may help identify higher-risk individuals with BD for personalized treatment and research. https://cobysuicideattemptsrc.shinyapps.io/Shiny.

Data that influence policy and major investment decisions risk entrenching social and political inequities.

Gentle stroking of the skin is a common social touch behavior with positive affective consequences. A preference for slow versus fast stroking of hairy skin has been closely linked to the firing of unmyelinated C-tactile (CT) somatosensory afferents. Because the firing of CT afferents strongly correlates with touch pleasantness, the CT pathway has been considered a social-affective sensory pathway. Recently, ablation of the spinothalamic pathway- thought to convey all C-fiber sensations- in patients with cancer pain impaired pain, temperature, and itch, but not ratings of pleasant touch. This suggested integration of afferent A and CT fiber input in the spinal cord, or mechanoreceptive A-fiber contributions to computations of touch pleasantness in the brain. However, contribution of mechanoreceptive A-fibers to touch pleasantness, in humans without pain, remains unknown. In the current, single-blinded study, we performed two types of peripheral nerve blocks in healthy adults to temporarily eliminate the contribution of A-fibers to touch perception. Our findings show that when mechanoreceptive A-fiber function is greatly diminished, the perceived intensity and pleasantness of both gentle stroking and deep pressure are nearly abolished. These findings demonstrate that explicit perception of the pleasantness of CT-targeted brushing and pressure both critically depend on afferent A-fibers.

BACKGROUND: Extracranial multisystem organ failure is a common sequela of severe traumatic brain injury (TBI). Risk factors for developing circulatory shock and long-term functional outcomes of this patient subset are poorly understood. OBJECTIVE: To identify emergency department predictors of circulatory shock after moderate-severe TBI and examine long-term functional outcomes in patients with moderate-severe TBI who developed circulatory shock. METHODS: We conducted a retrospective cohort study using the Transforming Clinical Research and Knowledge in TBI database for adult patients with moderate-severe TBI, defined as a Glasgow Coma Scale (GCS) score of

Identifying rates at which birders engage with different species can inform the impact and efficacy of conservation outreach and the scientific use of community-collected biodiversity data. Species that are thought to be “charismatic” are often prioritized in conservation, and previous researchers have used sociological experiments and digital records to estimate charisma indirectly. In this study, we take advantage of community science efforts as another record of human engagement with animals that can reveal observer biases directly, which are in part driven by observer preference. We apply a multistage analysis to ask whether opportunistic birders contributing to iNaturalist engage more with larger, more colorful, and rarer birds relative to a baseline approximated from eBird contributors. We find that body mass, color contrast, and range size all predict overrepresentation in the opportunistic dataset. We also find evidence that, across 472 modeled species, 52 species are significantly overreported and 158 are significantly underreported, indicating a wide variety of species-specific effects. Understanding which birds are highly engaging can aid conservationists in creating impactful outreach materials and engaging new naturalists. The quantified differences between two prominent community science efforts may also be of use for researchers leveraging the data from one or both of them to answer scientific questions of interest.

BackgroundTo identify prospectively ascertained individual and family factors that are associated with improvement in Bipolar Disorder (BD) among youths who initially presented with poor course.Methods82 youths with BD with persistent poor mood symptomatology ("predominantly ill course") were compared to 70 youths with BD who at intake had poor course, but showed improvement during the follow-up ("ill with improving course"), (ages 12.3 ± 3.3, vs. 11.7 ± 3.3 years old, at intake). Improvement was measured by the percentage of time euthymic during a mean follow-up of 12.8 years. Youths and parents were interviewed to assess psychopathology, functioning, treatment, and familial functioning and psychopathology.ResultsCompared to the ill group, since intake, the improving group showed significantly lower subthreshold depression and hypo/mania, Attention Deficit Hyperactivity Disorder, and Disruptive Behavior Disorders. Parental Socioeconomic Status (SES) remained unchanged over time in the ill group, but progressively increased in the improving group. Importantly, the change in SES predated the improvement in the mood trajectory. The most influential variables that predicted improvement were higher SES, and absence of parental BD and Substance Use Disorder (SUD). Parental SUD also negatively affected the parental SES, which was directly associated with worse mood course.LimitationsPredominantly self-reported White samples may limit generalizability; other factors potentially associated with outcome (e.g., treatment adherence), were not ascertained.ConclusionsIn addition to treating mood/comorbid psychopathology in symptomatic BD youths, to improve their prognosis, it is crucial to address their parent's BD and SUD and promote parental education/employment.

BACKGROUND: Childhood abuse negatively impacts the course of Bipolar Disorder (BD). Yet, no study has examined risk factors associated with prospectively evaluated physical/sexual abuse, specifically, those preceding first abuse among BD youth. We investigate past/intake/follow-up factors preceding first physical/sexual abuse among BD youth. METHODS: Childhood-onset BD participants (n = 279 youth, mean age at intake = 12, mean length of follow-up = 12 years) enrolled in the Course and Outcome of Bipolar Youth (COBY) study. Demographic, clinical and family history variables were assessed every 7 months on average using Longitudinal Interval Follow-up Evaluation and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Abuse was evaluated at intake using the K-SADS-PL, over follow-up with a Traumatic Events Screen. Family psychopathology was assessed using Family History Screen/Structured Clinical Interview for Diagnostic Statistical Manual-IV. RESULTS: Fifteen-percent of youth reported new-onset abuse during follow-up (62% physical, 26% sexual; 12% both). Intake predictors included more severe depressive symptoms (HR = 1.29), low socioeconomic-status (SES) in families with substance abuse (HR = 0.84) (physical abuse), and female sex (HR = 2.41) (sexual abuse). Follow-up predictors preceding physical abuse included: older age (HR = 1.42), disruptive disorders (HR = 1.39), and the interaction between low SES and family substance abuse (HR = 0.86). For sexual abuse, female sex (HR = 4.33) and a non-biologically related father presence in the household (HR = 2.76). Good relationships with friends (prospectively evaluated) protected against physical/sexual abuse (HR = 0.72/0.70, respectively). LIMITATIONS: Prospective data was gathered longitudinally but assessed retrospectively at every follow-up; perpetrator information and abuse severity were not available. CONCLUSIONS: Identifying factors temporally preceding new onset physical/sexual abuse may hold promise for identifying high-risk youth with BD.

BackgroundEarly hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury.MethodsWe conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

ObjectivesTraumatic brain injury is a leading cause of death and disability in the United States. While the impact of early multiple organ dysfunction syndrome has been studied in many critical care paradigms, the clinical impact of early multiple organ dysfunction syndrome in traumatic brain injury is poorly understood. We examined the incidence and impact of early multiple organ dysfunction syndrome on clinical, functional, and disability outcomes over the year following traumatic brain injury.DesignRetrospective cohort study.SettingPatients enrolled in the Transforming Clinical Research and Knowledge in Traumatic Brain Injury study, an 18-center prospective cohort study of traumatic brain injury patients evaluated in participating level 1 trauma centers.SubjectsAdult (age > 17 yr) patients with moderate-severe traumatic brain injury (Glasgow Coma Scale < 13). We excluded patients with major extracranial injury (Abbreviated Injury Scale score ≥ 3).InterventionsDevelopment of early multiple organ dysfunction syndrome, defined as a maximum modified Sequential Organ Failure Assessment score greater than 7 during the initial 72 hours following admission.Measurements and main resultsThe main outcomes were: hospital mortality, length of stay, 6-month functional and disability domains (Glasgow Outcome Scale-Extended and Disability Rating Scale), and 1-year mortality. Secondary outcomes included: ICU length of stay, 3-month Glasgow Outcome Scale-Extended, 3-month Disability Rating Scale, 1-year Glasgow Outcome Scale-Extended, and 1-year Disability Rating Scale. We examined 373 subjects with moderate-severe traumatic brain injury. The mean (sd) Glasgow Coma Scale in the emergency department was 5.8 (3.2), with 280 subjects (75%) classified as severe traumatic brain injury (Glasgow Coma Scale 3-8). Among subjects with moderate-severe traumatic brain injury, 252 (68%) developed early multiple organ dysfunction syndrome. Subjects that developed early multiple organ dysfunction syndrome had a 75% decreased odds of a favorable outcome (Glasgow Outcome Scale-Extended 5-8) at 6 months (adjusted odds ratio, 0.25; 95% CI, 0.12-0.51) and increased disability (higher Disability Rating Scale score) at 6 months (adjusted mean difference, 2.04; 95% CI, 0.92-3.17). Subjects that developed early multiple organ dysfunction syndrome experienced an increased hospital length of stay (adjusted mean difference, 11.4 d; 95% CI, 7.1-15.8), with a nonsignificantly decreased survival to hospital discharge (odds ratio, 0.47; 95% CI, 0.18-1.2).ConclusionsEarly multiple organ dysfunction following moderate-severe traumatic brain injury is common and independently impacts multiple domains (mortality, function, and disability) over the year following injury. Further research is necessary to understand underlying mechanisms, improve early recognition, and optimize management strategies.

ObjectivesWhile adults with bipolar disorder (BD) often report symptoms starting in childhood, continuity of mania and/or hypomania (mania/hypomania) from childhood to adulthood has been questioned. Using longitudinal data from the Course and Outcome of Bipolar Youth (COBY) study, we assessed threshold mania/hypomania in young adults who manifested BD as youth.MethodsCOBY is a naturalistic, longitudinal study of 446 youth with BD (84% recruited from outpatient clinics), 7-17 years old at intake, and over 11 years of follow-up. Focusing on youth with BD-I/II (n = 297), we examined adult mania/hypomania risk (>18 years old; mean 7.9 years of follow-up) according to child (

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

BackgroundYouth with bipolar disorder (BD) are at high risk for suicidal thoughts and behaviors and frequently experience interpersonal impairment, which is a risk factor for suicide. Yet, no study to date has examined the longitudinal associations between relationship quality in family/peer domains and suicidal thoughts and behaviors among youth with BD. Thus, we investigated how between-person differences - reflecting the average relationship quality across time - and within-person changes, reflecting recent fluctuations in relationship quality, act as distal and/or proximal risk factors for suicidal ideation (SI) and suicide attempts.MethodsWe used longitudinal data from the Course and Outcome of Bipolar Youth Study (N = 413). Relationship quality variables were decomposed into stable (i.e., average) and varying (i.e., recent) components and entered, along with major clinical covariates, into separate Bayesian multilevel models predicting SI and suicide attempt. We also examined how the relationship quality effects interacted with age and sex.ResultsPoorer average relationship quality with parents (β = -.33, 95% Bayesian highest density interval (HDI) [-0.54, -0.11]) or friends (β = -.33, 95% HDI [-0.55, -0.11]) was longitudinally associated with increased risk of SI but not suicide attempt. Worsening recent relationship quality with parents (β = -.10, 95% HDI [-0.19, -0.03]) and, to a lesser extent, friends (β = -.06, 95% HDI [-0.15, 0.03]) was longitudinally associated with increased risk of SI, but only worsening recent relationship quality with parents was also associated with increased risk of suicide attempt (β = -.15, 95% HDI [-0.31, 0.01]). The effects of certain relationship quality variables were moderated by gender but not age.ConclusionsAmong youth with BD, having poorer average relationship quality with peers and/or parents represents a distal risk factor for SI but not suicide attempts. Additionally, worsening recent relationship quality with parents may be a time-sensitive indicator of increased risk for SI or suicide attempt.

BackgroundPediatric bipolar disorders are often characterized by disruptions in cognitive functioning, and exposure to child maltreatment (e.g., physical and sexual abuse) is associated with a significantly poorer course of illness. Although clinical and developmental research has shown maltreatment to be robustly associated with poorer cognitive functioning, it is unclear whether maltreatment and cognitive function jointly influence the clinical course of bipolar symptoms.MethodsThis secondary analysis examined moderating effects of lifetime childhood physical and sexual abuse, and cognitive disruptions (sustained attention, affective information processing), on longitudinal ratings of depression symptom severity in youths from the Course and Outcome of Bipolar Youth (COBY) study, examined from intake (M = 12.24 years) through age 22 (N = 198; 43.9% female; Mean age of bipolar onset = 8.85 years).ResultsA significant moderating effect was detected for sustained attention and maltreatment history. In the context of lower sustained attention, maltreatment exposure was associated with higher depression symptom severity during childhood, but not late adolescence. There was no association between maltreatment and symptom severity in the context of higher sustained attention, and no association between attention and depression symptom severity for non-maltreated youths.LimitationsDepression symptom ratings at each assessment were subject to retrospective recall bias despite the longitudinal design. Cognitive assessments were administered at different ages across youths.ConclusionsDepressive symptoms in pediatric bipolar may be jointly moderated by impairments in attention and exposure to maltreatment. Assessment of these risks, particularly in childhood, may be beneficial for considering risk of recurrence or chronicity of depressive symptoms.

OBJECTIVE: With each recurrence the prognosis of bipolar disorder (BD) worsens, indicating the need to identify the factors associated with increased recurrence risk. The course of BD is heterogenous and although risk factors for recurrence for the group as a whole have been reported in the literature, identification of risk factors for a specific individual are crucial for developing personalized treatments. METHOD: A total of 363 recovered BD youths/young adults from the Course and Outcome of Bipolar Youth (COBY) study were included. Participants were evaluated on average every 7 months for a median of 12.5 years and interviewed with standard instruments. Risk factors of recurrence from the literature were used to build a risk calculator (RC) to predict recurrence risk at different time intervals. RESULTS: Approximately 80% of participants had at least one syndromal recurrence and 60% had ≥2 recurrences, particularly depressions. The 6-month and 1-, 2-, 3-, and 5-year RC showed an accuracy between 72% and 82% for predicting any mood recurrences, and up to 80% for depression and 89% for hypo/mania (sensitivity/specificity both 0.74). The most influential recurrence risk factors were shorter recovery lengths, younger age at assessment, earlier mood onset, and more severe prior depression. Although important, other factors associated with recurrence risk, such as interepisodic subsyndromal mood symptoms and comorbidities, did not influence the RC score beyond factors noted above. CONCLUSION: The RC provides a useful tool for predicting an individuals recurrence risk of depression and/or hypo/mania in BD youths and for developing personalized interventions and informing research. Replication studies are warranted.

ObjectiveLithium is the mainstay for bipolar disorder (BD) treatment in adults, but evidence in youths is limited. We used data from the Course and Outcome of Bipolar Youth (COBY) study to assess whether lithium vs other mood-stabilizing medication (OMS) was associated with improved outcomes, including mood symptoms and suicidality.MethodCOBY is a naturalistic, longitudinal study of 413 youths, 7 to 17.11 years old at intake, with BD. At each visit, medication exposure, psychiatric symptoms, and psychosocial function over the preceding follow-up period were assessed using the Adolescent Longitudinal Interval Follow-Up Evaluation. Using mixed models, we determined whether participants taking lithium vs OMS (but not lithium) differed regarding mood symptoms, suicidality, psychosocial function, hospitalization, aggression, and substance use.ResultsA total of 340 participants contributed 2,638 six-month follow-up periods (886 lithium, 1,752 OMS), over a mean follow-up of 10 years. During lithium (vs OMS) follow-up periods, participants were older, less likely to have lifetime anxiety, and less likely to be on antidepressants (p values

BACKGROUND: Exposure to severe Traumatic Events (TEs) has been associated with poor course and outcomes among individuals with Bipolar Disorder (BD). However, there is limited research on TEs among youth with BD, and few studies are longitudinal. This study prospectively followed a large sample of BD youth, examining the associations of lifetime TEs with their mood and functioning. METHODS: BD participants (n=375; mean age=17; range 8-25y) were assessed, on average, every 7 months for a median 8.7 years. Psychopathology and lifetime trauma history were prospectively evaluated using the Longitudinal Interval Follow-Up Evaluation, and a traumatic events screening. RESULTS: Accounting for covariates, participants with one or more lifetime TEs (84%) showed earlier BD onset, poorer psychosocial functioning, worse mood symptoms, and more suicidal ideation, comorbidities, and family psychopathology than those without TEs. TEs during recovery periods increased recurrence risk (p

ObjectivesThe association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment.MethodsAn international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps.ResultsThe association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets.ConclusionsFurther research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

BackgroundDespite the well-documented negative impact of untreated bipolar illness, approaches to early intervention in childhood-onset bipolar and related disorders are not well delineated.MethodsWe reviewed the extant treatment literature on children at high risk for bipolar disorder, with definitions based on family history, childhood adversity, and prodromal symptoms.ResultsA panoply of approaches have been described, but most interventions are based on an inadequate database to support their routine implementation. We classify early stage interventions as a function of their safety and tolerability with the hope that these might generate more rigorous study and a stronger database.LimitationsCritics may rightly argue that identifying viable treatment methods is premature given our lack of ability to reliably predict illness trajectory in very young children. However, many of the psychosocial and pharmacological interventions we present could have nonspecific positive effects across a variety of symptoms, syndromes, and diagnoses, further enhancing the rationale for more rigorous study.ConclusionsEarly stage interventions have the potential to improve functioning in prodromal illness and exert long-term positive effects on the course of illness. Many of the safest interventions deserve consideration for implementation and dissemination studies.

OBJECTIVES: Compare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5). METHODS: Participants from the parent Course and Outcome of Bipolar Youth study (N = 446) were assessed utilizing The Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), KSADS Mania Rating Scale (KMRS), and KSADS Depression Rating Scale (KDRS). Youth were grouped at baseline into those with increased energy (meeting DSM-5 Criteria A for mania) vs. without increased energy (meeting DSM-IV, but not DSM-5, Criteria A for mania), for those who had worst lifetime mood episode recorded (n = 430). Youth with available longitudinal data had the presence/absence of increased energy measured, as well as psychiatric symptomatology/clinical outcomes (evaluated via the Adolescent Longitudinal Interval Follow-Up Evaluation), at each follow-up for 12.5 years (n = 398). RESULTS: At baseline, the increased energy group (based on endorsed increased energy during worst lifetime mood episode; 86% of participants) vs. the without increased energy group, were more likely to meet criteria for BD-I and BD Not Otherwise Specified, had higher KMRS/KDRS total scores, and displayed poorer family/global psychosocial functioning. However, frequency of increased energy between groups was comparable after 5 years, and no significant group differences were found on clinical/psychosocial functioning outcomes after 12.5 years. LIMITATIONS: Secondary data limited study design; groupings were based on one time point. CONCLUSIONS: Results indicate no clinically relevant longitudinal group differences.

ObjectivesCompare longitudinal trajectories of youth with Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Bipolar Disorder (BD), grouped at baseline by presence/absence of increased energy during their worst lifetime mood episode (required for DSM-5).MethodsParticipants from the parent Course and Outcome of Bipolar Youth study (N = 446) were assessed utilizing The Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), KSADS Mania Rating Scale (KMRS), and KSADS Depression Rating Scale (KDRS). Youth were grouped at baseline into those with increased energy (meeting DSM-5 Criteria A for mania) vs. without increased energy (meeting DSM-IV, but not DSM-5, Criteria A for mania), for those who had worst lifetime mood episode recorded (n = 430). Youth with available longitudinal data had the presence/absence of increased energy measured, as well as psychiatric symptomatology/clinical outcomes (evaluated via the Adolescent Longitudinal Interval Follow-Up Evaluation), at each follow-up for 12.5 years (n = 398).ResultsAt baseline, the increased energy group (based on endorsed increased energy during worst lifetime mood episode; 86% of participants) vs. the without increased energy group, were more likely to meet criteria for BD-I and BD Not Otherwise Specified, had higher KMRS/KDRS total scores, and displayed poorer family/global psychosocial functioning. However, frequency of increased energy between groups was comparable after 5 years, and no significant group differences were found on clinical/psychosocial functioning outcomes after 12.5 years.LimitationsSecondary data limited study design; groupings were based on one time point.ConclusionsResults indicate no clinically relevant longitudinal group differences.

OBJECTIVES: Few studies have examined domain-specific psychosocial functioning in Bipolar Disorder (BD) youths. This prospective study examines (1) Interpersonal Relationships with Family; (2) Interpersonal Relationships with Friends; (3) School/Work; (4) Recreation; (5) Life Satisfaction, in BD youths. METHOD: A Course and Outcome of Bipolar Youth subsample (n = 367; mean intake age = 12.6 years, SD = 3.3; 46.6% female) was previously grouped into 4 Classes based on their illness trajectories and percentage of time euthymic using Latent Class Growth Analysis: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning within the domains were examined for greater than 10 years using the Adolescent Longitudinal Interval Follow-Up Evaluation. RESULTS: Class 1 demonstrated better functioning across all domains; Class 4 demonstrated worse functioning across all domains. Class 2 showed worsening relationships and recreation, and improvement in work/schoolwork. Class 3 showed variable domain declines and improvements. Despite symptomatic remission, 13%-20% of Class 1 and 20-47% of Classes 1/3 still had impairments across different domains. Early age of BD onset impacted impairment across most domains, and low SES significantly predicted impairment in family relationships. LIMITATIONS: The study does not have a healthy control group to compare functioning findings. CONCLUSIONS: Participants with more symptomatic mood trajectories had greater impairment across domains. Moreover, even with symptomatic remission, participants still exhibited impairment. Each Class and domain had different trajectories for impairment. Results suggest the importance of examining specific (vs. global) domains for targeted treatment, even when symptomatically remitted.

ObjectivesFew studies have examined domain-specific psychosocial functioning in Bipolar Disorder (BD) youths. This prospective study examines (1) Interpersonal Relationships with Family; (2) Interpersonal Relationships with Friends; (3) School/Work; (4) Recreation; (5) Life Satisfaction, in BD youths.MethodA Course and Outcome of Bipolar Youth subsample (n = 367; mean intake age = 12.6 years, SD = 3.3; 46.6% female) was previously grouped into 4 Classes based on their illness trajectories and percentage of time euthymic using Latent Class Growth Analysis: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning within the domains were examined for greater than 10 years using the Adolescent Longitudinal Interval Follow-Up Evaluation.ResultsClass 1 demonstrated better functioning across all domains; Class 4 demonstrated worse functioning across all domains. Class 2 showed worsening relationships and recreation, and improvement in work/schoolwork. Class 3 showed variable domain declines and improvements. Despite symptomatic remission, 13%-20% of Class 1 and 20-47% of Classes 1/3 still had impairments across different domains. Early age of BD onset impacted impairment across most domains, and low SES significantly predicted impairment in family relationships.LimitationsThe study does not have a healthy control group to compare functioning findings.ConclusionsParticipants with more symptomatic mood trajectories had greater impairment across domains. Moreover, even with symptomatic remission, participants still exhibited impairment. Each Class and domain had different trajectories for impairment. Results suggest the importance of examining specific (vs. global) domains for targeted treatment, even when symptomatically remitted.

OBJECTIVES: To compare the longitudinal clinical course of youths with bipolar disorder (BD) spectrum with lifetime (past, intake, and/or follow-up) psychosis (BDP+) to youths with BD without lifetime psychosis (BDP-). Also, to identify risk factors associated with increased risk of first onset of psychosis during prospective follow-up. METHOD: Bipolar disorder youths (BDP+ = 137, BDP- = 233), aged 7-17 years old, were followed on average every 7 months for 11.7 years and were evaluated using standardized instruments. Data were analyzed using linear and generalized linear models for the full sample, as well as for youths who developed first period of psychosis (n = 55). RESULTS: After adjusting for confounders, BDP+ youths with one, and in particular ≥2 lifetime psychotic episodes, had higher rates and more severe mood and anxiety symptoms, higher rates of suicidality, psychiatric hospitalizations, and sexual/physical abuse, and poorer psychosocial functioning than BDP- youths. Even before the first onset of psychosis during follow-up, BDP+ youths showed more psychopathology and had more family history of psychiatric illness than those who never developed psychosis. First-onset psychosis was associated with low socioeconomic status (SES), living with one parent, bipolar disorder type one and type two, comorbid anxiety, history of hospitalizations, and family history of mania and suicidality. CONCLUSION: BDP+ is associated with poor prognosis and worse clinical picture, even before the onset of psychosis, indicating the need for prompt identification and treatment of these youths. Studies aimed to treat acute symptoms of psychosis, as well as prevent the onset of psychosis, including risk factors amenable to change, are warranted.

ObjectiveDespite substantial literature on sex differences in adults with bipolar disorder (BD), little is known about this topic in youth; this study examines sex differences in mood symptomatology and psychiatric comorbidity in prospectively followed youth with BD.MethodsA subsample of the Course and Outcome of Bipolar Youth study (N = 370; female n = 199, male n = 171) enrolled October 2000-July 2006 (age at intake = 7-17.11 years) who met DSM-IV criteria for bipolar I disorder (BD-I; n = 221), bipolar II disorder (BD-II; n = 26), or operationalized BD not otherwise specified (BD-NOS; n = 123) with ≥ 4 years follow-up was included. Analyses examined sex differences at intake and, prospectively, in mood symptomatology and psychiatric comorbidity for a mean ± SD follow-up of 10.5 ± 1.72 years.ResultsFemales were older than males at intake (mean ± SD age = 13.33 ± 3.32 vs 12.04 ± 3.16 years; P = .0002) and at age at mood onset (9.33 ± 4.22 vs 7.53 ± 3.74 years; P < .0001). After adjustment for confounders, males spent more time with syndromal ADHD (Padjusted = .001) and females spent more time with syndromal anxiety (Padjusted = .02). There were trends toward males spending more time with substance use disorder and females having more non-suicidal self-injurious behavior (Padjusted = .07 and .09, respectively). There were no sex differences on outcome variables, including rate of or time to recovery and recurrence.ConclusionsContrasting with adult literature, this study identified minimal sex differences in the course of youth with BD. Longer-term studies are needed to clarify if youth-onset BD remains a "sex neutral" subtype of BD or diverges according to sex in adulthood.

ObjectiveTo compare the longitudinal course of family functioning in offspring of parents with bipolar disorder (BD), offspring of parents with non-BD psychopathology, and offspring of healthy control (HC) parents.MethodOffspring of parents with BD (256 parents and 481 offspring), parents without BD (82 parents and 162 offspring), and HC parents (88 parents and 175 offspring) 7 to 18 years of age at intake, from the Bipolar Offspring Study (BIOS), were followed for an average of 4.3 years. Family functioning was evaluated using the child- and parent-reported Family Adaptability and Cohesion Scale-II and the Conflict Behavior Questionnaire. The data were analyzed using multivariate multilevel regression, generalized linear estimating equation models, and path analysis.ResultsFamilies of parents with BD and parents with non-BD psychopathology showed lower cohesion and adaptability and higher conflict compared with HC families. There were no significant differences in cohesion and adaptability between families of parents with psychopathology. The effect of parental psychopathology on family functioning was mediated by parental psychosocial functioning and, to a lesser extent, offspring disorders. In all 3 groups, parent-reported family conflict was significantly higher than child-reported conflict. Across groups, family cohesion decreased over follow-up, whereas conflict increased.ConclusionAny parental psychopathology predicted family impairment. These results were influenced by the offspring's age and were mediated by parental psychosocial functioning and, to a lesser degree, by offspring psychopathology. These findings emphasize the need to routinely assess family functioning in addition to psychopathology and provide appropriate interventions to parents and offspring.

ObjectivesIn a sample of participants diagnosed with Bipolar Disorder (BD) in youth, we aim: (1) to examine longitudinal psychosocial functioning; (2) to determine whether psychosocial impairment remains in those who remitted from mood disorders during later periods of follow-up; (3) to examine predictors of psychosocial impairment despite symptomatic remission.MethodA Course and Outcome of Bipolar Youth subsample of 367 (≥ 4 years follow-up data) were grouped into mood trajectories: Class 1 Predominantly Euthymic; Class 2 Moderately Euthymic; Class 3 Ill with Improving Course; Class 4 Predominantly Ill. Psychosocial functioning was assessed via Children's Global Assessment Scale (C-GAS) for those under age 22; Global Assessment of Functioning (GAF) scale after 22. Current school, employment, and disability status were examined. Established predictors of symptomatic impairment were analyzed.ResultsThe Predominantly Euthymic Class had better psychosocial functioning, and were more likely to be in school/employed. The Persistently Ill Class had worse psychosocial functioning, and were more likely to receive disability. However, 44% of Predominantly Euthymic and 93% of Ill with Improving Course participants continued to experience current psychosocial impairment. Early BD onset, low Socioeconomic Status (SES), and current comorbidity, predicted poor psychosocial functioning. Low SES, and current comorbidity, predicted no school enrollment/unemployment.LimitationsThe study does not have a healthy control group to compare functioning findings.ConclusionsIn general, youth with persistent mood symptoms had worse psychosocial functioning, moreover, those with remitted symptoms still exhibited current psychosocial functioning deficits. High risk individuals with predictors of impairment should be targeted for functioning interventions.

ObjectiveDespite abundant literature demonstrating increased metabolic syndrome (MetS) prevalence and important clinical correlates of MetS among middle-age adults with bipolar disorder, little is known about this topic among adolescents and young adults early in their course of bipolar disorder. We therefore examined this topic in the Course and Outcome of Bipolar Youth (COBY) study.MethodsA cross-sectional, retrospective study was conducted of 162 adolescents and young adults (mean ± SD age = 20.8 ± 3.7 years; range, 13.6-28.3 years) with bipolar disorder (I, II, or not otherwise specified, based on DSM-IV) enrolled in COBY between 2000 and 2006. MetS measures (blood pressure, glucose, high-density lipoprotein cholesterol [HDL-C], triglycerides, and waist circumference), defined using the International Diabetes Federation criteria, were obtained at a single timepoint. Mood, comorbidity, and treatment over the 6 months preceding the MetS assessment were evaluated using the Longitudinal Interval Follow-Up Evaluation.ResultsThe prevalence of MetS in the sample was 19.8% (32/162). Low HDL-C (56.5%) and abdominal obesity (46.9%) were the most common MetS criteria. MetS was nominally associated with lower lifetime global functioning at COBY intake (odds ratio [OR] = 0.97, P = .06). MetS was significantly associated with percentage of weeks in full-threshold pure depression (OR = 1.07, P = .02) and percentage of weeks receiving antidepressant medications (OR = 1.06, P = .001) in the preceding 6 months. MetS was not associated with manic symptoms or medications other than antidepressants.ConclusionsThe prevalence of MetS in this sample was at least double compared to the general population. Moreover, MetS is associated with increased burden of depression symptoms in this group. Management of early-onset bipolar disorder should integrate strategies focused on modifying MetS risk factors.

ObjectiveMost studies of pediatric bipolar disorder (BP) combine youth who have manic symptoms, but do not meet criteria for BP I/II, into one "not otherwise specified" (NOS) group. Consequently, little is known about how youth with cyclothymic disorder (CycD) differ from youth with BP NOS. The objective of this study was to determine whether youth with a research diagnosis of CycD (RDCyc) differ from youth with operationalized BP NOS.MethodParticipants from the Course and Outcome of Bipolar Youth study were evaluated to determine whether they met RDCyc criteria. Characteristics of RDCyc youth and BP NOS youth were compared at baseline, and over eight-years follow-up.ResultsOf 154 youth (average age 11.96 (3.3), 42% female), 29 met RDCyc criteria. RDCyc youth were younger (p = .04) at baseline. Over follow-up, RDCyc youth were more likely to have a disruptive behavior disorder (p = .01), and were more likely to experience irritability (p = .03), mood reactivity (p = .02), and rejection sensitivity (p = .03). BP NOS youth were more likely to develop hypomania (p = .02), or depression (p = .02), and tended to have mood episodes earlier in the eight-year follow-up period.LimitationsRDCyc diagnoses were made retrospectively and followed stringent criteria, which may highlight differences that, under typical clinical conditions and more vague criteria, would not be evident.ConclusionThere were few differences between RDCyc and BP NOS youth. However, the ways in which the groups diverged could have implications; chronic subsyndromal mood symptoms may portend a severe, but ultimately non-bipolar, course. Longer follow-up is necessary to determine the trajectory and outcomes of CycD symptoms.

ObjectiveYouth with subthreshold mania are at increased risk of conversion to bipolar disorder (BP) I/II. Predictors for conversion have been published for the group as a whole. However, risk factors are heterogeneous, indicating the need for personalized risk assessment.MethodOne hundred forty youth with BP not otherwise specified (BP-NOS; 6-17 years old) followed through the Course and Outcome of Bipolar Youth (COBY) study with at least 1 follow-up assessment before conversion to BP-I/II were included. Youths were assessed on average every 7 months (median 11.5 years) using standard instruments. Risk predictors reported in the literature were used to build a 5-year risk calculator. Discrimination was measured using the time-dependent area under the curve after 1,000 bootstrap resamples. Calibration was evaluated by comparing observed with predicted probability of conversion. External validation was performed using an independent sample of 58 youths with BP-NOS recruited from the Pittsburgh Bipolar Offspring Study.ResultsSeventy-five (53.6%) COBY youths with BP-NOS converted to BP-I/II, of which 57 (76.0%) converted within 5 years. Earlier-onset BP-NOS, familial hypomania/mania, and high mania, anxiety, and mood lability symptoms were important predictors of conversion. The calculator showed excellent consistency between the predicted and observed risks of conversion, good discrimination between converters and non-converters (area under the curve 0.71, CI 0.67-0.74), and a proportionally increasing rate of converters at each successive risk class. Discrimination in the external validation sample was good (area under the curve 0.75).ConclusionIf replicated, the risk calculator would provide a useful tool to predict personalized risk of conversion from subsyndromal mania to BP-I/II and inform individualized interventions and research.

ObjectiveThis study aims to document rates of sexual activity among youth with bipolar spectrum disorder (BD) and to examine demographic and clinical factors associated with first sexual activity and sexual risk behavior during follow-up.MethodThe sample was drawn from the Course and Outcome of Bipolar Youth (COBY) study of 413 youth 7 to 17 years at baseline who met criteria for bipolar spectrum disorder according to the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Psychiatric symptoms during follow-up were assessed using the Adolescent Longitudinal Interview Follow-Up Evaluation (ALIFE). Sexual behavior and level of sexual risk (e.g., unprotected sex, multiple partners, and/or partners with known sexually transmitted infections) were assessed by trained evaluators using the ALIFE Psychosocial Functioning Scale. Analyses were conducted in relation to first sexual behavior during follow-up and then to subsequent sexual behaviors (mean 9.7 years, standard deviation 3.2).ResultsSexually active COBY youth (n = 292 of 413; 71%) were more likely females, using substances, and not living with both parents. Consistent with findings among healthy youth, earlier first sexual activity in the sample was significantly associated with low socioeconomic status, female sex, comorbid disruptive behavior disorder, and substance use. As with healthy youth, sexual risk behavior during follow-up was significantly associated with non-Caucasian race, low socioeconomic status, substance use, and history of sexual abuse. Of those COBY youth who were sexually active, 11% reported sexual assault or abuse, 36% reported becoming pregnant (or the significant other becoming pregnant), and 15% reported having at least 1 abortion (or the significant other having an abortion) during follow-up. Hypomanic symptoms during follow-up were temporally associated with the greatest risk for sexual risk behavior.ConclusionDemographic and clinical factors could help identify youth with bipolar spectrum disorder at significantly greatest risk for sexual activity and sexual risk behavior. Attending to sexual risk behaviors in this population is warranted.

ObjectivesOver the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings.MethodsAn international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps.ResultsSubstantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD.ConclusionsAs data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

BackgroundDifferences in NICU quality of care provided to very low birth weight (

ObjectiveThere is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables.MethodCognitive functioning was measured in 135 participants from the Course and Outcome of BP Youth (COBY) study using several subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Youth were prospectively evaluated three times on average every 13.75 months over 2.5 years. Clinical and functional outcomes were assessed using the Longitudinal Interval Follow-Up Evaluation (LIFE).ResultsLatent class growth analysis identified three longitudinal patterns of cognitive functioning based on a general cognitive index: class 1, "persistently high" (N=21; 15.6%); class 2, "persistently moderate" (N=82; 60.74%); and class 3, "persistently low" (N=32; 23.7%). All classes showed normal cognitive functioning when compared with the CANTAB normative data. After adjustment for confounders, youth from class 3 had a significantly greater percentage of time with overall, manic, and depressive syndromal symptoms than youth in the other two classes. Also, after adjustment for confounders, youth from class 3 had significantly poorer global, academic, and social functioning than youth from class 1.ConclusionsBP youth showed normal overall cognitive functioning that remained stable during the follow-up within each class. However, 24% of BP youth showed poorer cognitive functioning than the other BP youth. This subgroup had poorer mood course and functioning, and may benefit from cognitive remediation and early management with evidence-based pharmacological treatments.

ObjectivesTo identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode.MethodsYouth with BP (N = 30) were compared with youth with unipolar depression (N = 59) during an acute depressive episode using the depression and mania items derived from the Schedule for Affective Disorders and Schizophrenia for Children (K-SADS)-Present Version. The results were adjusted for multiple comparisons, and any significant between-group differences in demographic, nonmood comorbid disorders, and psychiatric family history.ResultsIn comparison with unipolar depressed youth, BP depressed youth had significantly higher scores in several depressive symptoms and all subsyndromal manic symptoms, with the exception of increased goal-directed activity. Among the depressive symptoms, higher ratings of nonsuicidal physical self-injurious acts and mood reactivity, and lower ratings of aches/pains, were the symptoms that best discriminated BP from unipolar depressed youth. Subsyndromal manic symptoms, particularly motor hyperactivity, distractibility, and pressured speech, were higher in BP depressed youth and discriminated BP depressed from unipolar depressed youth.ConclusionsThe results of this study suggest that it is possible to differentiate BP depression from unipolar depression based on depressive symptoms, and in particular subsyndromal manic symptoms. If replicated, these results have important clinical and research implications.

ObjectiveTo provide the first longitudinal characterization of mood and psychosocial functioning in youth with comorbid bipolar (BD) and autism spectrum (ASD) disorders.MethodThe Course and Outcome of Bipolar Youth study followed 368 youth (aged 7-17 years) with DSM-IV bipolar I (BP-I), BP-II, or Not Otherwise Specified (NOS) for, on average, 9 years using the Longitudinal Interval Follow-up Evaluation. This subgroup analysis compared youth with and without ASD on clinical presentation, percentage of time with mood symptomatology, and psychosocial functioning.ResultsThirty youth (∼8%) met DSM-IV criteria for Asperger's disorder or pervasive developmental disorder-NOS (referred to here as ASD). Lifetime worst episode severity was similar in both groups, but youth with both BD and ASD (BD+ASD) had elevated rates of comorbid attention-deficit/hyperactivity and obsessive-compulsive disorders, were younger at intake, and had an earlier onset of mood symptoms. Over time, in both groups, the proportion of predominantly euthymic youth increased, and episode recurrence decreased. Compared to youth with BD, the clinical presentation of youth with BD+ASD more frequently involved distractibility, racing thoughts, depressed mood, social withdrawal, and low reactivity of negative mood states. ASD-related symptomatic differences were generally strongest early and decreased over time. Youth with BD+ASD had significantly greater impairment in friendships throughout follow-up.ConclusionYouth with BD+ASD exhibit typical BD mood symptoms but with earlier onset, mixed symptom presentation, and additive functional impairments. Significant amelioration of clinical symptoms occurred over time, suggesting that early recognition and treatment of mood disorders in youth with ASD may improve clinical outcomes.

Comparing the relative fit of competing models can be used to address many different scientific questions. In classical statistics one can, if appropriate, use likelihood ratio tests and information based criterion, whereas clinical medicine has tended to rely on comparisons of fit metrics like C-statistics. However, for many data adaptive modelling procedures such approaches are not suitable. In these cases, statisticians have used cross-validation, which can make inference challenging. In this paper we propose a general approach that focuses on the "conditional" risk difference (conditional on the model fits being fixed) for the improvement in prediction risk. Specifically, we derive a Wald-type test statistic and associated confidence intervals for cross-validated test sets utilizing the independent validation within cross-validation in conjunction with a test for multiple comparisons. We show that this test maintains proper Type I Error under the null fit, and can be used as a general test of relative fit for any semi-parametric model alternative. We apply the test to a candidate gene study to test for the association of a set of genes in a genetic pathway.

BackgroundRegionalized care delivery purportedly optimizes care to vulnerable very low birth weight (VLBW;

BackgroundGenome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.MethodsWe analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).FindingsNine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.InterpretationThese results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

ObjectiveDespite burgeoning literature in middle-aged adults, little is known regarding proinflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore retrospectively examined these topics in the Course and Outcome of Bipolar Youth (COBY) study.MethodSubjects were 123 adolescents and young adults (mean [SD] = 20.4 ± 3.8 years; range, 13.4-28.3 years) in COBY, enrolled between October 2000 and July 2006. DSM-IV diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Clinical characteristics during the preceding 6 months, including mood, comorbidity, and treatment, were evaluated using the Longitudinal Interval Follow-Up Evaluation (LIFE). Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hsCRP) were assayed. Primary analyses examined the association of PIMs with bipolar disorder characteristics during the preceding 6 months.ResultsSeveral lifetime clinical characteristics were significantly associated with PIMs in multivariable analyses, including longer illness duration (P = .005 for IL-6; P = .0004 for hsCRP), suicide attempts (P = .01 for TNF-α), family history of suicide attempts or completion (P = .01 for hsCRP), self-injurious behavior (P =.005 for TNF-α), substance use disorder (SUD) (P < .0001 for hsCRP), and family history of SUD (P = .02 for TNF-α; P = .01 for IL-6). The following bipolar disorder characteristics during the preceding 6 months remained significantly associated with PIMs in multivariable analyses that controlled for differences in comorbidity and treatment: for TNF-α, percentage of weeks with psychosis (χ(2) = 5.7, P =.02); for IL-6, percentage of weeks with subthreshold mood symptoms (χ(2)= 8.3, P = .004) and any suicide attempt (χ(2) = 6.1, P = .01); for hsCRP, maximum severity of depressive symptoms (χ(2) = 8.3, P =.004).ConclusionProinflammatory markers may be relevant to bipolar disorder characteristics as well as other clinical characteristics among adolescents and young adults with bipolar disorder. Traction toward validating PIMs as clinically relevant biomarkers in bipolar disorder will require repeated measures of PIMs and incorporation of relevant covariates.

BackgroundComorbid substance use disorders (SUD) are associated with increased illness severity and functional impairment among adolescents with bipolar disorder (BD). Previous psychosocial treatment studies have excluded adolescents with both BD and SUD. Studies suggest that integrated interventions are optimal for adults with BD and SUD.MethodsWe modified family-focused treatment for adolescents with BD (FFT-A) in order to explicitly target comorbid SUD (FFT-SUD). Ten adolescents with BD who had both SUD and an exacerbation of manic, depressed, or mixed symptoms within the last 3 months were enrolled. FFT-SUD was offered as an adjunct to pharmacotherapy, with a target of 21 sessions over 12 months of treatment. The FFT- SUD manual was iteratively modified to integrate a concurrent focus on SUD.ResultsSix subjects completed a mid-treatment 6-month assessment (after a mean of 16 sessions was completed). Of the 10 subjects, 3 dropped out early (after ≤1 session); in the case of each of these subjects, the participating parent had active SUD. No other subjects in the study had a parent with active SUD. Preliminary findings suggested significant reductions in manic symptoms and depressive symptoms and improved global functioning in the subjects who completed 6 months of treatment. Reduction in cannabis use was modest and did not reach significance. Limitations. Limitations included a small sample, open treatment, concurrent medications, and no control group.ConclusionsThese preliminary findings suggest that FFT-SUD is a feasible intervention, particularly for youth without parental SUD. FFT-SUD may be effective in treating mood symptoms, particularly depression, despite modest reductions in substance use. Integrating motivation enhancing strategies may augment the effect of this intervention on substance use. Additional strategies, such as targeting parental substance use, may prevent early attrition.

ImportanceWhole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.ObjectivesTo examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.Design, setting, and participantsAn exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Main outcomes and measuresGenome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.ResultsDepending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P

ObjectiveTo examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP).MethodAs part of the Course and Outcome of Bipolar Youth study, 413 youth, who were 7 through 17 years or age and who met criteria for DSM-IV BP-I (n = 244), BP-II (n = 28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n = 141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed.ResultsAt intake and during the follow-up, 62% of youth with BP met criteria for at least 1 anxiety disorder. About 50% of the BP youth with anxiety had ≥2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety.ConclusionsAnxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, and more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted.

ObjectiveMortality associated with acute lung injury remains high. Early identification of acute lung injury prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score identifies patients at risk for acute lung injury but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of early acute lung injury to identify patients with lung injury prior to the need for positive pressure ventilation.DesignProspective observational cohort study.SettingStanford University Hospital.PatientsWe prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.InterventionsNone.Measurements and main resultsOf the 256 patients enrolled, 62 patients (25%) progressed to acute lung injury requiring positive pressure ventilation. Clinical variables (through first 72 hr or up to 6 hr prior to acute lung injury) associated with progression to acute lung injury were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to acute lung injury. A simple three-component early acute lung injury score (1 point for oxygen requirement > 2-6 L/min or 2 points for > 6 L/min; 1 point each for a respiratory rate ≥ 30 and immune suppression) accurately identified patients who progressed to acute lung injury requiring positive pressure ventilation (area under the receiver-operator characteristic curve, 0.86) and performed similarly to the Lung Injury Prediction Score. An early acute lung injury score greater than or equal to 2 identified patients who progressed to acute lung injury with 89% sensitivity and 75% specificity. Median time of progression from early acute lung injury criteria to acute lung injury requiring positive pressure ventilation was 20 hours.ConclusionsThis pragmatic definition of early acute lung injury accurately identified patients who progressed to acute lung injury prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of acute lung injury.

BackgroundCurrent regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation.Methods and resultsA single experienced reviewer interpreted the first ECG obtained after brain stem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002 to 2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft use for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy, prolongation of the corrected QT interval, and repolarization changes (ST/T wave abnormalities). Fifty-seven percent of potential cardiac allografts in this cohort were accepted for transplantation. Left ventricular hypertrophy on ECG was a strong predictor of allograft nonuse. No significant associations were seen among corrected QT interval prolongation, repolarization changes, and allograft use for transplantation after adjusting for donor clinical variables and echocardiographic findings.ConclusionsWe have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brain stem herniation and are not associated with allograft use for transplantation.