Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study.

INTRODUCTION/AIMS: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported. METHODS: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. RESULTS: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. DISCUSSION: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

A Critical Appraisal of Matching-Adjusted Indirect Comparisons in Spinal Muscular Atrophy.

In the absence of head-to-head trials, indirect treatment comparisons (ITCs) are often used to compare the efficacy of different therapies to support decision-making. Matching-adjusted indirect comparison (MAIC), a type of ITC, is increasingly used to compare treatment efficacy when individual patient data are available from one trial and only aggregate data are available from the other trial. This paper examines the conduct and reporting of MAICs to compare treatments for spinal muscular atrophy (SMA), a rare neuromuscular disease. A literature search identified three studies comparing approved treatments for SMA including nusinersen, risdiplam, and onasemnogene abeparvovec. The quality of the MAICs was assessed on the basis of the following principles consolidated from published MAIC best practices: (1) justification for the use of MAIC is clearly stated, (2) the included trials with respect to study population and design are comparable, (3) all known confounders and effect modifiers are identified a priori and accounted for in the analysis, (4) outcomes should be similar in definition and assessment, (5) baseline characteristics are reported before and after adjustment, along with weights, and (6) key details of a MAIC are reported. In the three MAIC publications in SMA to date, the quality of analysis and reporting varied greatly. Various sources of bias in the MAICs were identified, including lack of control for key confounders and effect modifiers, inconsistency in outcome definitions across trials, imbalances in important baseline characteristics after weighting, and lack of reporting key elements. These findings highlight the importance of evaluating MAICs according to best practices when assessing the conduct and reporting of MAICs.

Examining Real-World Adherence to Nusinersen for the Treatment of Spinal Muscular Atrophy Using Two Large US Data Sources.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare neuromuscular disease characterized by progressive muscular atrophy and weakness. Nusinersen was the first treatment approved for SMA. Per the US label, the nusinersen administration schedule consists of three loading doses at 14-day intervals, a fourth loading dose 30 days later, and maintenance doses every 4 months thereafter. Using two large US databases, we evaluated real-world adherence to nusinersen with its unique dosing schedule among generalizable populations of patients with SMA. METHODS: Patients with SMA treated with nusinersen, likely to have complete information on date of treatment initiation, were identified in the Optum® de-identified electronic health records (EHR) database (7/2017-9/2019), and in the Merative™ MarketScan® Research Databases from commercial (1/2017-6/2020) and Medicaid claims (1/2017-12/2019). Baseline demographics, number of nusinersen administrations on time, and distribution of inter-dose intervals were summarized. RESULTS: Totals of 67 and 291 patients were identified in the EHR and claims databases, respectively. Most nusinersen doses were received on time (93.9% EHR, 80.5% claims). Adherence was higher during the maintenance phase (90.6%) than the loading phase (71.1%) in the claims analysis, in contrast with the EHR analysis (95.5% and 92.6%, respectively), suggesting that not all loading doses of nusinersen may be accurately captured in claims. Inter-dose intervals captured in both databases aligned with the expected dosing schedule. CONCLUSION: Most nusinersen doses were received on time, consistent with the recommended schedule. Our findings also highlight the importance of careful methodological approaches when using real-world administrative databases for evaluation of nusinersen treatment patterns.

Adherence to medicines in the real world is important for patients with chronic disease to see long-term benefits of treatment. This study shows the importance and challenges of measuring adherence using real-world administrative data sources. This is especially important for drugs given through lumbar puncture with unique dosing schedules, such as nusinersen for the treatment of spinal muscular atrophy. In this study, most patients with spinal muscular atrophy received their nusinersen doses on time.

Real-world Adherence to Nusinersen in Adults with Spinal Muscular Atrophy in the US: A Multi-site Chart Review Study.

Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US centers between January 2017 and February 2019. Seventy-nine (92%) adults remained on nusinersen during the study; 454 (92%) of 493 total nusinersen doses were received on time. Fifty-eight (67%) adults received all nusinersen doses on time. The majority of patients with at least one nonadherent dose resumed nusinersen on time. Most patients followed the dosing schedule across the loading and maintenance dose periods.

Characterization of Adult Patients With SMA Treated in US Hospital Settings: A Natural History Study in the Premier Healthcare Database.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disease characterized by progressive muscular weakness and atrophy resulting from motor neuron degeneration. Limited information is available on disease progression among older SMA patients, particularly adults. OBJECTIVE: This study sought to characterize the natural history of SMA among adult patients in US hospital settings through the assessment of symptoms, complications, costs, and healthcare resource utilization (HRU) over 3 years before the availability of disease-modifying therapies. METHODS: The study population included adult (≥18 years) patients with inpatient and/or hospital-based outpatient discharge records and ≥2 primary or secondary SMA ICD-9 codes ≥30 days apart in the Premier Healthcare Database during the main study period (2007-2014). Index date was the date of the first SMA ICD-9 code. The frequency of SMA-related symptoms and complications was assessed 1 year preindex through 2 years postindex to characterize disease progression. Costs and HRU were also assessed across the study period. RESULTS: A total of 446 adult patients from 337 US hospitals met inclusion criteria for these analyses. All evaluated SMA-related symptoms and complications increased steadily over time, from 1 year preindex to 2 years postindex both overall and in each age group. Adult patients with SMA had increasing total costs and HRU over the 3-year study period: total costs were $1,759 preindex and $12,308 by 2 years postindex. CONCLUSIONS: Findings are consistent with increasing disease burden over time and support the progressive nature of SMA for adult patients with hospital interactions.

The Cure SMA Membership Surveys: Highlights of Key Demographic and Clinical Characteristics of Individuals with Spinal Muscular Atrophy.

BACKGROUND: Cure SMA maintains the largest patient-reported database for people affected with spinal muscular atrophy (SMA). In 2017, Cure SMA initiated annual surveys with their membership to collect demographic and disease characteristics, healthcare, and burden of disease information from patients and caregivers. OBJECTIVE: To summarize results from two large-scale Cure SMA surveys in 2017 and 2018. METHODS: Cure SMA database members were invited to complete surveys; these were completed by caregivers for living or deceased individuals with SMA and/or affected adults. RESULTS: In 2017, 726 surveys were completed for 695 individuals with SMA; in 2018, 796 surveys were completed for 760 individuals with SMA. Data from both survey years are available for 313 affected individuals. Age at symptom onset, distribution of SMN2 gene copy number, and representation of each SMA type in the surveys were consistent with that expected in the SMA population. In the 2018 survey, the average age at diagnosis was 5.2 months for SMA type I and the reported mean age at death for this subgroup was 27.8 months. Between survey years, there was consistency in responses for factors that should not change within individuals over time (e.g., reported age at diagnosis). CONCLUSIONS: Results from the Cure SMA surveys advance the understanding of SMA and facilitate advocacy efforts and healthcare services planning. Longitudinal surveys are important for evaluating the impact of effective treatments on changing phenotypes, and burden of disease and care in individuals with SMA.

Maternal smoking during pregnancy and offspring antisocial behaviour: findings from a longitudinal investigation of discordant siblings.

BACKGROUND: Although many observational studies have found a strong association between maternal smoking during pregnancy (MSP) and offspring antisocial behaviour, the likelihood that this relationship is causal remains unclear. To comment on the potential causality of this association, the current investigation used a between-within decomposition approach to examine the association between MSP and multiple indices of adolescent and adult antisocial behaviour. METHODS: Study participants were offspring of women enrolled in the Providence and Boston sites of the Collaborative Perinatal Project. Information on MSP was collected prospectively. Antisocial behaviour was assessed via self-report and through official records searches. A subset of the adult offspring (average age: 39.6 years) were enrolled in a follow-up study oversampling families with multiple siblings. Participants in this follow-up study self-reported on juvenile and adult antisocial behaviours during a structured interview (n=1684). Official records of juvenile (n=3447) and adult (n=3433) criminal behaviour were obtained for participants in the Providence cohort. Statistical models allowed between-family effects of MSP exposure to differ from within-family effects. In the absence of heterogeneity in between-family versus within-family estimates, a combined estimate was calculated. RESULTS: MSP was associated with a range of antisocial behaviours, measured by self-report and official records. For example, MSP was associated with increased odds of elevated levels of antisocial behaviours during adolescence and adulthood, as well as violent and non-violent outcomes during both developmental periods. CONCLUSIONS: Findings are consistent with a small-to-moderate causal effect of MSP on adolescent and adult antisocial behaviour.

Impact of persistent and adolescent-limited antisocial behaviour on adult health outcomes.

BACKGROUND: Persistent engagement in antisocial behaviour across developmental periods is thought to increase the risk for early disease morbidity. However, less is known about potential adverse health outcomes among the much larger subset of individuals with antisocial behaviour limited to adolescence. METHODS: Using data from the Providence, Rhode Island cohort of the Collaborative Perinatal Project, we examined the association between developmentally based subtypes of antisocial behaviour and health outcomes (n=801). Official arrest records and self-reports of engagement in antisocial behaviour were used to classify participants into antisocial groups (persistent into adulthood, adolescent-limited, no significant problems) that were contrasted across important adult health indicators. RESULTS: With few exceptions, those with persistent antisocial behaviour had the highest prevalence of each health problem. Compared to those with no antisocial behaviour, participants with persistent problems had poorer overall health and significantly elevated odds of cardiovascular problems, wheezing, lower back pain, cancer, serious injury and emergency department visits. Those with adolescent-limited behaviour experienced significantly increased odds of health concerns including poorer overall health, hypercholesterolaemia, acute respiratory problems and wheezing, lower back pain and emergency department visits compared to participants with no antisocial behaviour. Both antisocial groups reported barriers to healthcare access. CONCLUSIONS: Findings highlight the impact of persistent antisocial behaviour on adult health, and suggest that antisocial behaviour limited to adolescence is also an important marker of poor health. Given that antisocial behaviour during adolescence is an important early marker of adverse health outcomes, youth exhibiting serious behavioural problems should be targeted for preventive interventions.

A prospective investigation of neurodevelopmental risk factors for adult antisocial behavior combining official arrest records and self-reports.

Neurodevelopmental deficits are postulated to play an important role in the etiology of persistent antisocial behavior (ASB). Yet it remains uncertain as to which particular deficits are most closely associated with ASB. We seek to advance this understanding using prospectively collected data from a birth cohort in which multiple indices of neurodevelopmental functioning and ASB were assessed. Participants (n = 2776) were members of the Providence, Rhode Island cohort of the Collaborative Perinatal Project. Information on demographic and neurodevelopmental variables was collected from pregnancy through age 7. When all offspring had reached 33 years of age an adult criminal record check was conducted. A subset of subjects also self-reported on their engagement in serious ASB. Bivariate logistic regression was used to examine the relationship between each neurodevelopmental factor and adult ASB and test whether associations varied depending on how ASB was ascertained. After controlling for background and contextual characteristics, maternal smoking during pregnancy, lower childhood verbal and performance IQ, and age 7 aggressive/impulsive behavior all significantly increased the odds of adult ASB. Associations were not modified by sex and did not depend on how ASB was assessed. However, while both males and Black participants were more likely to engage in ASB than their respective female and White counterparts, relationships were significantly stronger for official records than for self-reports. Results point to a particular subset of early neurodevelopmental risks for antisocial outcomes in adulthood. Findings also suggest that prior contradictory results are not due to the use of official records versus self-reported outcomes.

Prevalence of schizophrenia disability and associated mortality among Chinese men and women.

Schizophrenia is a major cause of psychiatric disability in China. In the present study, we estimated total and age-specific prevalence of both schizophrenia disability and associated mortality among Chinese women and men. We further examined whether sex differences in prevalence were attributable to mortality differences between men and women. Data from the Second China National Sample Survey on Disability (2006) and the 2007-2010 follow-up studies were utilized. Possibly psychiatrically disabled individuals were administered the World Health Organization Disability Assessment Schedule, Version II and the ICD-10 Symptom Checklist for Mental Disorders by trained clinical psychiatrists. In total, 0.37% of men and 0.44% of women were living with schizophrenia disability in China. We did not find statistically significant differences in the 4-year cumulative mortality between men and women. Overall standardized mortality ratios for the age groups of 18-29, 30-39, 40-49, 50-59, 60-69, and 70+ years were 120.89, 29.56, 15.06, 9.16, 10.57, and 4.95, respectively. In conclusion, mortality differences between men and women were unlikely to be a major contributor to sex differences in prevalence. Premature death among younger individuals experiencing schizophrenia disability warrants urgent attention.

Maternal smoking, breastfeeding, and risk of childhood overweight: findings from a national cohort.

To examine the association between exposure to tobacco compounds in breast milk and risk of childhood overweight, we used historical data for a subset of 21,063 mother-child pairs in the US Collaborative Perinatal Project. Based on self-reports, mothers were classified as non-smokers, light (1-9 cigarettes/day), moderate (10-19), or heavy (20+) smokers. Feeding type (exclusive breastfeeding or bottle-feeding) was observed during nursery stay after birth. We stratified children by maternal smoking and feeding type, and then fit interaction terms to isolate exposure to tobacco compounds via breast milk from exposure in uterus and in ambient air after birth. Using measured weight and height, overweight at age 7 was defined as a body mass index ≥85th percentile by sex and age. Among exclusively bottle-fed children, adjusted odds ratios (ORs) of overweight at age 7 were 1.24 (95% confidence interval [CI], 1.12-1.38; vs. non-smoking) for light maternal smoking, 1.43 (95% CI, 1.25-1.63) for moderate maternal smoking, and 1.46 (95% CI, 1.28-1.66) for heavy maternal smoking. Among exclusively breastfed children, the corresponding ORs were 1.33 (95% CI, 0.96-1.84) for light, 1.86 (95% CI, 1.27-2.73) for moderate, and 2.22 (95% CI, 1.53-3.20) for heavy maternal smoking. There was a modest positive interaction between breastfeeding and heavy maternal smoking on overweight risk at age 7. Tobacco compounds via breast milk of smoking mothers (significantly for heavy smokers) appear to be associated with a modest elevation in childhood overweight risk at 7 years of age. More aggressive intervention is needed to help pregnant and breastfeeding women to quit smoking.

Childhood impulsive behavior and problem gambling by adulthood: a 30-year prospective community-based study.

AIMS: Problem gambling can create major financial, emotional and sometimes criminal problems for an individual. This study prospectively investigated the association between impulsive behavior at age 7 and the development of life-time problem gambling by adulthood. We also examined the specificity of any observed association between impulsive behaviors and problem gambling by conducting parallel analyses examining the link between respondents' shy/depressed behavior in childhood and later problem gambling. DESIGN, SETTING AND PARTICIPANTS: Cohort study of 958 offspring of mothers enrolled in the Collaborative Perinatal Project who participated in an adult follow-up study at a mean age of 39.2 years. MEASUREMENTS: Multivariable logistic regression models were fitted to determine associations between psychologist-rated impulsive and shy/depressed behaviors at age 7 and life-time self-reported gambling as measured by the South Oaks Gambling Screen administered during the adult follow-up study. FINDINGS: Children who exhibited impulsive behaviors at age 7, compared to their non-impulsive counterparts, were 3.09 (95% confidence interval: 1.40-6.82) times as likely to report problem gambling years later. In contrast, we did not find a significant association between childhood shy/depressed behavior and problem gambling by adulthood in adjusted analyses. CONCLUSIONS: Impulsive behaviors at age 7 are a specific and significant risk factor for later problem gambling.

Adolescent Family Factors Promoting Healthy Adult Functioning: A Longitudinal Community Study.

BACKGROUND: Although long-held wisdom and current research suggests that accepting and supportive family relationships may positively influence adult psychosocial functioning, few studies have prospectively investigated these associations. This study examined whether positive family factors during adolescence are associated with healthy adult functioning. METHOD: The 353 participants were part of a single-age cohort whose psychosocial development has been prospectively traced. Two aspects of family functioning - feeling highly valued as a family member and having a family confidant - were measured at age 15. Developmentally-relevant areas of functioning were assessed at age 30. RESULTS: Both positive family factors were predictive of adaptive adult functioning across several domains, including mental health and social/interpersonal functioning. CONCLUSIONS: Findings provide evidence about the salient relationships between positive family relationships and later healthy functioning.

Maternal smoking during pregnancy and criminal offending among adult offspring.

BACKGROUND: Although a number of previous studies have reported an association between maternal smoking during pregnancy (MSP) and externalising behaviour problems among offspring, it has been suggested that this relationship is spurious due to the failure of these studies to properly account for important confounding factors. METHODS: The relationship between MSP and adult criminal offending was examined using data from 3766 members of the Providence, Rhode Island, cohort of the Collaborative Perinatal Project. Information on MSP and most potential confounders was collected prospectively throughout pregnancy. In 1999-2000 all offspring had reached 33 years of age and an adult criminal record check was performed. Because previous research has been criticised for not properly accounting for confounding influences, our primary aim was to determine whether the MSP-criminal offending relationship held after efficiently adjusting for a wide range of sociodemographic and family background characteristics using propensity score methods. RESULTS: The association between MSP and adult criminal offending remained after controlling for propensity scores. Offspring of mothers who smoked heavily during pregnancy (≥20 cigarettes per day) had the greatest odds of an adult arrest record (OR 1.31, 95% CI 1.06 to 1.62). Findings also suggest that MSP may be an independent risk factor for adult criminal histories marked by multiple arrests. Lastly, our findings show that the impact of MSP operates similarly across both genders. CONCLUSION: Results from this study provide evidence of an association between heavy MSP and long-term criminal offending. Any causal association is likely to be weak to moderate in strength.

Long-term impact of family arguments and physical violence on adult functioning at age 30 years: findings from the simmons longitudinal study.

OBJECTIVE: To prospectively examine the extent to which an increase in family arguments by age 15 years and the occurrence of family physical violence by age 18 years are related to deficits in key domains of adult functioning at age 30 years. METHOD: The 346 participants were part of a single-age cohort from a predominately white working-class community whose psychosocial development has been traced since age 5 years. Family arguments and violence were assessed through self-reports during adolescence. Developmentally relevant areas of current adult functioning were measured by self-reports, structured diagnostic interviews, and clinical interviewer ratings. RESULTS: Both family arguments and physical violence were significantly related to compromised functioning across multiple areas of adult functioning. Although many associations were somewhat attenuated after controlling for sex, other early family adversities, and family history of disorder, most relations retained statistical significance. Both risk factors were linked with later mental health problems and deficits in psychological and occupational/career functioning. Family violence was also linked to poorer physical health at age 30 years. CONCLUSIONS: Findings underscore the potential long-term impact of troubled family interactions and highlight the critical importance of early intervention programs for youths experiencing either verbal conflict or physical violence in the home.

Major depression in the transition to adulthood: the impact of active and past depression on young adult functioning.

This study examined the association between active and past major depression and deficits in young adult functioning using data from a longitudinal community study (N = 354). Three groups were compared: (1) participants with a 1-year diagnosis of major depression at age 26 (active group); (2) those who experienced major depression during the transition to adulthood, ages 18-25, but did not have active depression at age 26 (past group); and (3) individuals not meeting diagnostic criteria for depression during the transition period. Results highlight serious deficits in psychosocial functioning at age 26 linked to both active and past depression. Although participants with active depression experienced the greatest number of problems, those with past depression evidenced similar deficits across many important domains of functioning. The significant impairments characterizing those with past depression indicate the need for continued monitoring to decrease the risk of recurrence and the establishment of a chronic course of illness.

Childhood and adolescent predictors of major depression in the transition to adulthood.

OBJECTIVE: The identification of predictors of major depression in the transition to adulthood has direct application to prevention and intervention efforts designed to forestall depression in this high-risk period. The current study identified childhood and adolescent familial and behavioral-emotional factors predicting depression during this critical developmental stage. METHOD: The 354 participants were part of a single-age cohort from a predominately Caucasian working-class community whose psychosocial development has been traced prospectively since age 5. In these analyses, data collected during childhood and adolescence were related to diagnoses of major depression at ages 18-26. RESULTS: During the transition to adulthood, 82 participants (23.2%) experienced major depression. Bivariate indicators of later depression included a family history of depression or substance use disorders, family composition, and childhood family environments perceived as violent and lacking cohesiveness. Also significant were self- and mother-reported internalizing behaviors, as well as self-rated anxiety and depressive symptoms. Multivariable analyses showed family violence, family composition, internalizing problems during adolescence, and low family cohesion to be the most salient factors. CONCLUSIONS: These results highlight familial and behavioral-emotional predictors of depression that can serve as foci for identifying youth in need of intervention.

Child and adolescent predictors for eating disorders in a community population of young adult women.

OBJECTIVE: This study investigated early predictors for developing eating disorders by young adulthood in a community sample of women participating in a 22-year longitudinal study. METHOD: Twenty-one women were identified at age 27 with lifetime full or partial eating disorders. These women were compared with 47 women with no history of eating disorders on predictive factors from three broad domains. RESULTS: The women with eating disorders had more serious health problems before age 5 and mother-reported anxiety-depression at age 9. At 15, mothers described them as having more behavior problems. Before age 15, families of the eating disorder group had more histories of depression, eating problems and changes in family financial circumstances. DISCUSSION: This study identifies early predictors distinguishing girls who develop eating disorders. Findings point to the need for continued research in the area of early health to comprehensively examine the biologic, behavioral, and environmental risks for eating disorders.