We retrospectively identified autism spectrum disorder (ASD) incident cases among 31,220 individuals in a population-based birth cohort based on signs and symptoms uniformly abstracted from medical and educational records. Inclusive and narrow research definitions of ASD (ASD-RI and ASD-RN, respectively) were explored, along with clinical diagnoses of ASD (ASD-C) obtained from the records. The incidence of ASD-RI, ASD-RN, and ASD-C increased significantly from 1985 to 1998, then ASD-RI and ASD-RN plateaued while the rate of ASD-C continued to increase during 1998–2004. The rising incidence of research-defined ASD may reflect improved recognition and documentation of ASD signs and symptoms. Although the frequency of threshold ASD symptoms stabilized, the rate of ASD-C continued to increase, narrowing the gap between clinical ascertainment and symptom documentation.

Objective: The objective of this study was to evaluate the effect of psychiatric comorbidities on the association between childhood ADHD and suicidality among adults. Method: Subjects were recruited from a population-based birth cohort. Participating adult subjects with childhood ADHD and non-ADHD controls were administered a structured psychiatric interview to assess suicidality and psychiatric comorbidities. Associations were assessed using logistic regression. Results: Compared with controls, ADHD cases were significantly more likely to meet criteria for suicidality. Subjects with childhood ADHD who met criteria for generalized anxiety disorder had a higher than expected risk of suicidality with an observed odds ratio of 10.94 (95% confidence interval [4.97, 24.08]) compared with an expected odds ratio of 4.86, consistent with a synergistic interaction effect. Significant synergistic interactions were also observed for hypomanic episode and substance-related disorders. Conclusion: Childhood ADHD is significantly associated with adult suicidal risk. Comorbidity between ADHD and some psychiatric disorders is associated with a higher suicidal risk than expected.

A large cohort consisting of all children born to mothers from community provides 'natural' selection into different exposures and is a powerful resource for epidemiological research. A large population-based birth cohort with detailed systematic information already recorded, as part of longitudinal medical care, historical and current school data, detailed birth certificate data and all three resources available for every member of the birth cohort, are extremely rare. Our population-based birth cohort consists of all children born between 1976 and 2000 to mothers residing in Olmsted County, Minnesota, at the time of child's birth (N=39 890). In this paper, we provide a comprehensive report of the method describing the identification, the characteristics and longitudinal follow-up of each child (and family members) from the birth cohort, wealth of complementary resources of data and study measures and designs (retrospective, combined retrospective/prospective). In the last decade or so, we obtained scientific and clinically needed answers for incidence rates, potential risk/protective factors, treatment, comorbidities, outcomes, cost/usage and potential biases (that are always assessed and clinically interpreted) of many developmental learning and behavioural disorders (DLBDs) including learning and attention-deficit/hyperactivity disorders, intellectual disability, speech-language impairment and autism spectrum disorder. Many current and future questions related to DLBDs are remaining to be answered. The Olmsted County Birth Cohort (OCBC) is an example of a comprehensive, contemporary epidemiological research model for the development of similar research infrastructures, and its current and future results are important for replication and comparison with other population-based retrospective and prospective birth cohort studies.

Background: Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes.Methods: A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models.Results: For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability.Conclusions: These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

Exposure to general anesthesia at an early age has been associated with adverse neurodevelopmental outcomes in both animal and human studies, but some of these studies employed anesthetic agents that are no longer in clinical use. In this manuscript, we describe the methods used to construct a new population-based study cohort to study the association between early anesthetic exposure and subsequent neurodevelopmental outcomes. A birth cohort of all children born in Olmsted County, MN from January 1, 1996 to December 31, 2000 was identified. For each, school enrollment status in the Independent School District (ISD) 535 at age 5 or 6 and all episodes of anesthetic exposure before age 3 were identified. A study cohort was created by matching children enrolled in ISD 535 based on the propensity of receiving general anesthesia. Three analyses were performed to characterize the study cohort by comparing the birth and parental information, comorbidities, and socioeconomic status. The first analysis compared the characteristics of birth cohort children who were and were not enrolled in ISD 535. The second analysis evaluated the success of the propensity matching schemes in creating groups of children that were similar in measured characteristics except for anesthesia exposure. The third analysis compared the characteristics of children with anesthesia exposures who were and were not included in the final cohort based on propensity matching. Results of these analyses demonstrate only slight differences among the comparison groups, and therefore these are unlikely to compromise our future analysis of anesthetic exposure and neurodevelopmental outcomes.

Seligman’s theory of causal attribution predicts that patients with a pessimistic explanatory style will have less favorable health outcomes. We investigated this hypothesis using self-reported hip pain and hip function 2- years after total hip arthroplasty (THA).

Objective To evaluate the mediating/moderating effects of common internalizing /externalizing disorders on the association between ADHD and adolescent substance use disorders (SUD) in a population-based birth cohort. Methods Among 5718 children in the birth cohort, 343 ADHD incident cases and 712 matched controls were identified. Psychiatric diagnoses prior to age 19 were classified into DSM-IV categories. The association between ADHD and SUD was summarized (hazard ratios (HR), 95% CI). The effect of depression, CD/ODD, anxiety was evaluated separately. Results Assessment of the joint effects of ADHD and each psychiatric disorder did not support a moderating effect of these disorders on SUD on additive scale. However, the association between ADHD and SUD was partially explained by a mediating role of these psychiatric disorders. Conclusion For clinicians our results emphasize that depression (or CD/ODD) confers greater risk for SUD than ADHD alone. Early detection/treatment of SUD among adolescents with depression (or CD/ODD) is crucial regardless of ADHD.

Objective: The aim of the study was to evaluate associations between ADHD and comorbid psychiatric disorders among adults from a population-based birth cohort. Method: Participants were recruited from all children born between 1976 and 1982 remaining in Rochester, Minnesota, after age 5. Participants with childhood ADHD ( n = 232; M age = 27.0 years; 72% men) and non-ADHD controls ( n = 335; M age = 28.6 years; 63% men) completed a structured interview (M.I.N.I. International Neuropsychiatric Interview) assessing current ADHD status and comorbid psychiatric disorders. Results: Among 232 with childhood ADHD, 68 (49 men, 19 women) had persistent adult ADHD. Compared with non-ADHD controls and non-persistent ADHD participants, adults with persistent ADHD were significantly more likely to have any or each of 12 psychiatric comorbidities. The associations retained significant or marginally significant when stratified by gender. Externalizing psychiatric disorders were more common in men (74%) and internalizing disorders in women (58%). Conclusion: Persistent ADHD is associated with an increased risk of comorbid psychiatric disorders in adult men and women.

OBJECTIVE:Previous research on the developmental course of attention-deficit/hyperactivity disorder (ADHD) is limited by biased clinic-referred samples and other methodological problems. Thus, questions about adult academic outcomes associated with childhood ADHD remain unanswered. Thus, the objective of this study was to describe academic outcomes in adulthood among incident cases of research-identified childhood ADHD versus non-ADHD referents from a population-based birth cohort.METHOD:Young adults with research-identified childhood ADHD (N = 232; mean age 27.0 yr; 72.0% men) and referents (N = 335; mean age 28.6 yr; 62.7% men) from a 1976 to 1982 birth cohort (N = 5699) were invited to participate in a followup study and were administered an academic achievement battery consisting of the basic reading component of the Woodcock-Johnson III Tests of Achievement (WJ-III) and the arithmetic subtest of the Wide Range Achievement Test-Third Edition (WRAT-3). Outcomes were compared between the 2 groups using linear regression models, adjusted for age, sex, and comorbid learning disability status.RESULTS:Childhood ADHD cases scored from 3 to 5 grade equivalents lower on all academic tests compared with referents, with mean (SD) standard scores of 95.7 (8.4) versus 101.8 (8.1) in basic reading; 95.0 (9.3) versus 101.9 (8.5) in letterword identification; 98.2 (8.6) versus 103.2 (9.2) in passage comprehension; 95.7 (9.1) versus 100.9 (9.0) in word attack; and 87.8 (12.9) versus 98.0 (12.0) in arithmetic.CONCLUSION:This is the first prospective, population-based study of adult academic outcomes of childhood ADHD. Our data provide evidence that childhood onset ADHD is associated with long-term underachievement in reading and math that may negatively impact ultimate educational attainment and occupational functioning in adulthood.

Background Psychosocial factors, such as pessimistic explanatory style, are shown to affect the course of treatments in many illnesses (Cardiovascular diseases, lung cancer, Parkinson9s disease). Little is known about how pessimistic explanatory style affects rheumatoid arthritis (RA). Objectives The aim of this study was to determine if pessimistic explanatory style altered the risk for and mortality rates of RA patients. Methods The study used a subset of patients who completed the Minnesota Multiphasic Personality Inventory (MMPI) from among a population-based cohort with incident RA in 1955–2007 and an age- and sex-matched non-RA comparison cohort. Only patients who were ≥18 and fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA were included. Pessimistic explanatory style was measured using the Optimism-Pessimism scale (PSM≥60). Logistic regression and Cox models were used to examine the associations between pessimistic explanatory style and development of RA or mortality rates. Results There were 148 RA and 135 non-RA subjects who completed the MMPI. Pessimistic explanatory style was associated with development of rheumatoid factor positive (RF+) RA (odds ratio [OR]:1.74; 95% confidence interval [CI]: 0.99–3.04; p=0.053 adjusted for age, sex, smoking and obesity). Among patients with RA, mortality risk adjusted for age, sex, year, smoking, and Charlson Comorbidity Index was increased with a pessimistic explanatory style (hazard ratio [HR]:2.88; 95%CI: 1.02–8.14), similar to mortality risk in RF+ RA patients (HR:2.28; 95%CI:1.10–4.73). A significant interaction between RF+ and pessimistic explanatory style indicated that having both did not confer an additive effect (p=0.037). The 10 year survival percentages were highest for those with RF-RA who were not pessimistic (93%) and were similar for patients with RF+RA who were not pessimistic (73%), those with RF-RA who were pessimistic (77%), and those who were both RF+RA and pessimistic (84%). This association did not change after adjusting for the MMPI depression scale or a history of depression prior to diagnosis of RA. Conclusions Having a pessimistic explanatory style was associated with an increased risk of developing RA and increased mortality rate in patients with RA. In these patients, the effects of RF+ and pessimistic style were not additive. The patient9s psychological state strongly affects treatment decisions and outcomes and can inform about the usefulness of mindful interventions (e.g. cognitive behavioral therapy). Understanding the explanatory style is an important step in the holistic management of disease and a vital component of integrated care. Disclosure of Interest None declared

Objective. To determine whether pessimistic explanatory style altered the risk for and mortality of patients with rheumatoid arthritis (RA).Methods. The study included subjects from a population-based cohort with incident RA and a non-RA comparison cohort who completed the Minnesota Multiphasic Personality Inventory.Results. Among 148 RA and 135 non-RA subjects, pessimism was associated with development of rheumatoid factor (RF)-positive RA. Pessimism was associated with an increased risk of mortality [HR 2.88 with similar magnitude to RF+ (HR 2.28)].Conclusion. Pessimistic explanatory style was associated with an increased risk of developing RA and increased mortality rate in patients with RA.

The purpose of this study was to offer detailed information about stimulant medication treatment provided throughout childhood to 379 children with research-identified attention-deficit hyperactivity disorder (ADHD) in the 1976-1982 Rochester, MN, birth cohort. Subjects were retrospectively followed from birth until a mean of 17.2 years of age. The complete medical record of each subject was reviewed. The history and results of each episode of stimulant treatment were compared by gender, DSM-IV subtype of ADHD, and type of stimulant medication. Overall, 77.8% of subjects were treated with stimulants. Boys were 1.8 times more likely than girls to be treated. The median age at initiation (9.8 years), median duration of treatment (33.8 months), and likelihood of developing at least one side effect (22.3%) were not significantly different by gender. Overall, 73.1% of episodes of stimulant treatment were associated with a favorable response. The likelihood of a favorable response was comparable for boys and girls. Treatment was initiated earlier for children with either ADHD combined type or ADHD hyperactive-impulsive type than for children with ADHD predominantly inattentive type and duration of treatment was longer for ADHD combined type. There was no association between DSM-IV subtype and likelihood of a favorable response or of side effects. Dextroamphetamine and methylphenidate were equally likely to be associated with a favorable response, but dextroamphetamine was more likely to be associated with side effects. These results demonstrate that the effectiveness of stimulant medication treatment of ADHD provided throughout childhood is comparable to the efficacy of stimulant treatment demonstrated in clinical trials.

Background: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are known to be at significantly greater risk for the development of substance use disorders (SUD) compared to peers. Impulsivity, which could lead to higher levels of drug use, is a known symptom of ADHD and likely accounts, in part, for this relationship. Other factors, such as a biologically increased susceptibility to substance dependence (addiction), may also play a role.Objective: This report further examines the relationships between childhood ADHD, adolescent-onset SUD, and substance abuse and substance dependence in adulthood.Method: Individuals with childhood ADHD and non-ADHD controls from the same population-based birth cohort were invited to participate in a prospective outcome study. Participants completed a structured neuropsychiatric interview with modules for SUD and a psychosocial questionnaire. Information on adolescent SUD was obtained retrospectively, in a previous study, from medical and school records. Associations were summarized using odds ratios (OR) and 95% CIs estimated from logistic regression models adjusted for age and gender.Results: A total of 232 ADHD cases and 335 non-ADHD controls participated (mean age, 27.0 and 28.6 years, respectively). ADHD cases were more likely than controls to have a SUD diagnosed in adolescence and were more likely to have alcohol (adjusted OR 14.38, 95% CI 1.49-138.88) and drug (adjusted OR 3.48, 95% CI 1.38-8.79) dependence in adulthood. The subgroup of participating ADHD cases who did not have SUD during adolescence were no more likely than controls to develop new onset alcohol dependence as adults, although they were significantly more likely to develop new onset drug dependence.Conclusions: Our study found preliminary evidence that adults with childhood ADHD are more susceptible than peers to developing drug dependence, a disorder associated with neurological changes in the brain. The relationship between ADHD and alcohol dependence appears to be more complex.

There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12years or 15 and 19years during the period 2012–2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks.

BACKGROUND AND OBJECTIVE:There is ongoing concern that stimulant medications may adversely affect growth. In a sample of attention-deficit/hyperactivity disorder (ADHD) cases and controls from a population-based birth cohort, we assessed growth and the association between stimulant treatment and growth.METHODS:Subjects included childhood ADHD cases (N = 340) and controls (N = 680) from a 1976 to 1982 birth cohort (N = 5718). Height and stimulant treatment information were abstracted from medical records and obtained during a prospective, adult follow-up study. For each subject, a parametric penalized spline smoothing method modeled height over time, and the corresponding height velocity was calculated as the first derivative. Peak height velocity (PHV) age and magnitude were estimated from the velocity curves. Among stimulant-treated ADHD cases, we analyzed height Z scores at the beginning, at the end, and 24 months after the end of treatment.RESULTS:Neither ADHD itself nor treatment with stimulants was associated with differences in magnitude of PHV or final adult height. Among boys treated with stimulants, there was a positive correlation between duration of stimulant usage before PHV and age at PHV (r = 0.21, P = .01). There was no significant correlation between duration of treatment and change in height Z scores (r = −0.08 for beginning vs end change, r = 0.01 for end vs 24 months later change). Among the 59 ADHD cases treated for ≥3 years, there was a clinically insignificant decrease in mean Z score from beginning (0.48) to end (0.33) of treatment (P = .06).CONCLUSIONS:Our findings suggest that ADHD treatment with stimulant medication is not associated with differences in adult height or significant changes in growth.

Objective To evaluate the association between ADHD and substance-related disorder (SRD) with and without depression, anxiety, conduct disorder and oppositional defiant disorder (CD/ODD) by age 19 years in a population-based birth cohort. Method Among 5718 children in a population-based birth cohort, 343 ADHD cases and 712 age-sex matched non-ADHD controls were identified in a previous study employing medical and school records. Psychiatric diagnoses were abstracted from the medical records and collapsed into the 10 categories based on DSM-IV. The association between ADHD case status and SRD was summarized by hazard ratios (HR) and corresponding 95% CI estimated from a Cox proportional hazards model. The effects of three psychiatric disorders (depression, anxiety, CD/ODD) were evaluated separately by considering each as a time-dependent covariate in a Cox regression model. Results ADHD was significantly associated with an increased risk of SRD (HR=3.70, 95% CI 2.51-5.46) by age 19 years. This association was observed in both boys and girls (HR=3.69 and 3.95, respectively). Among the boys without depression, ADHD was associated with four-fold increased risk of SRD, while the association was not present among boys with depression (HR= 4.07 vs. 0.98). Likewise, the association (HR) between ADHD case status and SRD was 0.78 and 3.77, respectively, among boys with and without CD/ODD. Conclusion The adverse effect of ADHD on SRD is more apparent for those without depression and conduct problems than it is for those with such comorbidities.

OBJECTIVE: This study reports the incidence of enuresis and encopresis among children with attention-deficit/hyperactivity disorder (ADHD) versus those without ADHD.METHODS: Subjects included 358 children (74.5% boys) with research-identified ADHD from a 1976 to 1982 population-based birth cohort (n = 5718) and 729 (75.2% boys) non-ADHD control subjects from the same birth cohort, matched by gender and age. All subjects were retrospectively followed from birth until a diagnosis of enuresis or encopresis was made or last follow-up before 18 years of age. The complete medical record for each subject was reviewed to obtain information on age of initial diagnosis of an elimination disorder, frequency and duration of symptoms, and identification of exclusionary criteria specified by DSM-IV, with confirmation of the diagnosis by expert consensus.RESULTS: Children with ADHD were 2.1 (95% confidence interval [CI], 1.3-3.4; P = .002) times more likely to meet DSM-IV criteria for enuresis than non-ADHD controls; they were 1.8 (95% CI, 1.2-2.7; P = .006) times more likely to do so than non-ADHD controls when less stringent criteria for a diagnosis of enuresis were employed. Though not significant, children with ADHD were 1.8 (95% CI, 0.7-4.6; P = .23) times more likely to meet criteria for encopresis than non-ADHD controls. The relative risk was 2.0 (95% CI, 1.0-4.1; P = .05) when a less stringent definition for encopresis was utilized.CONCLUSIONS: Children with ADHD are more likely than their peers without ADHD to develop enuresis with a similar trend for encopresis.

OBJECTIVE: We examined long-term outcomes of attention-deficit/hyperactivity disorder (ADHD) in a population-based sample of childhood ADHD cases and controls, prospectively assessed as adults. METHODS: Adults with childhood ADHD and non-ADHD controls from the same birth cohort (N = 5718) were invited to participate in a prospective outcome study. Vital status was determined for birth cohort members. Standardized mortality ratios (SMRs) were constructed to compare overall and cause-specific mortality between childhood ADHD cases and controls. Incarceration status was determined for childhood ADHD cases. A standardized neuropsychiatric interview was administered. RESULTS: Vital status for 367 childhood ADHD cases was determined: 7 (1.9%) were deceased, and 10 (2.7%) were currently incarcerated. The SMR for overall survival of childhood ADHD cases versus controls was 1.88 (95% confidence interval [CI], 0.83–4.26; P = .13) and for accidents only was 1.70 (95% CI, 0.49–5.97; P = .41). However, the cause-specific mortality for suicide only was significantly higher among ADHD cases (SMR, 4.83; 95% CI, 1.14–20.46; P = .032). Among the childhood ADHD cases participating in the prospective assessment (N = 232; mean age, 27.0 years), ADHD persisted into adulthood for 29.3% (95% CI, 23.5–35.2). Participating childhood ADHD cases were more likely than controls (N = 335; mean age, 28.6 years) to have ≥1 other psychiatric disorder (56.9% vs 34.9%; odds ratio, 2.6; 95% CI, 1.8–3.8; P < .01). CONCLUSIONS: Childhood ADHD is a chronic health problem, with significant risk for mortality, persistence of ADHD, and long-term morbidity in adulthood.