Search

Objective: Associations were examined between six psychiatric diagnoses in parents and a broad range of psychiatric and nonpsychiatric outcomes in their offspring. Methods: All individuals born in Sweden between 1970 and 2000 were linked to their biological parents (N=3,286,293) through Swedish national registers. A matched cohort design, with stratified Cox regression and conditional logistic regression analyses, was used examine associations between six psychiatric diagnoses in the parents and 32 outcomes in their offspring. All children, including those exposed and those not exposed to parents with psychiatric diagnoses, were followed from their date of birth to the date of emigration from Sweden, death, or December 31, 2013, when the offspring were 14–44 years old. Results: In terms of absolute risk, most children who had parents with psychiatric diagnoses were not diagnosed in specialist care themselves, and the proportion of offspring having any of the 16 types of psychiatric conditions ranged from 22.17% (of offspring exposed to parental depression) to 25.05% (of offspring exposed to parental drug-related disorder) at the end of follow-up. Nevertheless, in terms of relative risk, exposure to any of the six parental psychiatric diagnoses increased probabilities of the 32 outcomes among the offspring, with hazard ratios that ranged from 1.03 to 8.46 for time-to-event outcomes and odds ratios that ranged from 1.29 to 3.36 for binary outcomes. Some specificities were observed for parental diagnoses of psychosis and substance-related disorders, which more strongly predicted psychotic-like and externalizing-related outcomes, respectively, in the offspring. Conclusions: The intergenerational transmission of parental psychiatric conditions appeared largely transdiagnostic and extended to nonpsychiatric outcomes in offspring. Given the broad spectrum of associations with the outcomes, service providers (e.g., psychiatrists, teachers, and social workers) should consider clients' broader psychiatric family history when predicting prognosis and planning interventions or treatment. [ABSTRACT FROM AUTHOR]

Objective: Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability to psychopathology or confounded by unmeasured familial factors. The authors investigated the association between psychiatric conditions in young adulthood and the risk of cardiometabolic complications in middle adulthood, up to 40 years later. Methods: This cohort study (N=672,823) identified all individuals and their siblings born in Sweden between 1955 and 1962 and followed the cohort through 2013. Logistic regression models were used to estimate the bivariate associations between 10 psychiatric conditions or criminal convictions and five cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the comorbidity among psychiatric conditions and criminal convictions. The cardiometabolic complications were then regressed on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs. Results: Each psychiatric condition significantly increased the risk of cardiometabolic complications. These associations appeared nonspecific, as multivariate models indicated that most were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals' general psychopathology and their siblings' cardiometabolic complications. The same pattern was evident for the specific internalizing and psychotic factors. Conclusions: Associations between mental disorders in early life and later long-term risk of cardiometabolic complications appeared to be attributable to a general liability to psychopathology. Familial coaggregation analyses suggested that the elevated risk could not be attributed to confounders shared within families. One possibility is that lifestyle-based interventions may reduce the risk of later cardiometabolic complications for patients with several mental disorders. [ABSTRACT FROM AUTHOR]

Background: Proton radiotherapy treatment plans are currently restricted by the range uncertainties originating from the stopping power ratio (SPR) prediction based on single‐energy computed tomography (SECT). Various studies have shown that multi‐energy CT (MECT) can reduce the range uncertainties due to medical implant materials and age‐related variations in tissue composition. None of these has directly applied the basis material density (MD) images produced by projection‐based MECT systems for SPR prediction. Purpose: To present and evaluate a novel proton SPR prediction method based on MD images from dual‐energy CT (DECT), which could reduce the range uncertainties currently associated with proton radiotherapy. Methods: A theoretical basis material decomposition into water and iodine material densities was performed for various pediatric and adult human reference tissues, as well as other non‐tissue materials, by minimizing the root‐mean‐square relative attenuation error in the energy interval from 40 to 140 keV. A model (here called MD‐SPR) mapping predicted MDs to theoretically calculated reference SPRs was created with locally weighted scatterplot smoothing (LOWESS) data‐fitting. The goodness of fit of the MD‐SPR model was evaluated for the included reference tissues. MD images of two electron density phantoms, combined to form a head‐ and an abdomen‐sized phantom setup, were acquired with a clinical projection‐based fast‐kV switching DECT scanner. The MD images were compared to the theoretically predicted MDs of the tissue surrogates and other non‐tissue materials in the phantoms, as well as used for input to the MD‐SPR model for generation of SPR images. The SPR images were subsequently compared to theoretical reference SPRs of the materials in the phantoms, as well as to SPR images from a commercial algorithm (DirectSPR, Siemens Healthineers, Forchheim, Germany) using image‐based consecutive scan DECT for the same phantom setups. Results: The predicted SPRs of the tissue surrogates were similar for MD‐SPR and DirectSPR, where the adipose and bone tissue surrogates were within 1% difference to the reference SPRs, while other non‐adipose soft tissue surrogates (breast, brain, liver, muscle) were all underestimated by between −0.7% and −1.8%. The SPRs of the non‐tissue materials (polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), graphite and Teflon) were within 2.8% for MD‐SPR images, compared to 6.8% for DirectSPR. Conclusions: The MD‐SPR model performed similar compared to other published methods for the human reference tissues. The SPR prediction for tissue surrogates was similar to DirectSPR and showed potential to improve SPR prediction for non‐tissue materials. [ABSTRACT FROM AUTHOR]

All psychiatric phenomena are positively associated, and several different models can account for this observation. These include the correlated factors, network, general psychopathology as outcome, and hierarchical models. Advantages of hierarchical models, which consist of one general and several (general factor‐residualized) specific factors, is that the general factor provides an opportunity to reliably measure global distress and impairment, while the specific factors might improve the ability to discriminate between individuals with different kinds of problems. Nevertheless, other models also have their respective advantages, and it remains challenging to empirically determine which model best accounts for the positive manifold in psychiatry. Instead, I present two non‐empirical arguments in favor of hierarchical models. First, by measuring the general factor in isolation, the specific factors tend to include both favorable and unfavorable correlates, which might reduce stigma compared to psychiatric diagnoses that by and large are associated with only unfavorable outcomes. Second, the general psychopathology factor displays an unusual psychometric property in that it includes symptoms of opposite meaning if they have similar valence (e.g., self‐reported symptoms such as gullible and paranoid, lazy and workaholic, and terrified and apathetic load in the same direction), which one might want to measure in isolation from variance capturing the content of symptoms. I conclude by speculating that tests designed based on hierarchical models might help clinical assessment. [ABSTRACT FROM AUTHOR]

Key Points: Question: Are general and specific factors of psychopathology associated with 7 clinically relevant outcomes within adult sibling and twin pairs at 10-year follow-up? Findings: In this cohort study including 1 974 434 participants, general psychopathology was significantly associated with all 7 outcomes within sibling and dizygotic twin pairs and 3 outcomes within monozygotic twin pairs at 10 years. Within twin and sibling pairs, the specific factors were primarily associated with related outcomes. Meaning: The findings in this study suggest that associations cannot be attributed to unmeasured shared confounds, and interventions toward broad psychopathology dimensions might lead to a reduction in future clinically relevant events. This cohort study evaluates the association between psychopathology factors and clinically relevant outcomes at 10 years among twins and siblings. Importance: General and specific factors of psychopathology are associated with future adverse outcomes, indicating that they might be useful for identifying individuals at greatest risk. However, it remains unknown if these associations are attributable to confounders that may influence both the psychopathology factors and later outcomes. Objective: To analyze associations between psychopathology factors and clinically relevant outcomes within family pairs, adjusting for unmeasured confounds by applying co-twin control and sibling comparison designs. Design, Setting, and Participants: This longitudinal cohort study with a follow-up range of 9 to 13 years included all Swedish twins born from 1959 to 1985 who participated in the Study of Twin Adults: Genes and Environment (60% response rate) and the oldest pair of all Swedish siblings born from 1959 to 1985 per the Multi-Generation Register. Twins were evaluated based on responses to a hierarchical factor model derived using multivariate statistics. Sibling pairs were evaluated based on psychiatric diagnoses per the Swedish National Patient Register. Information on outcome events and prescriptions were derived from the National Patient Register, Prescribed Drug Register, and Crime Register. Baseline assessment was in August 2005, and data were analyzed from January 2022 to February 2023. Exposures: Hierarchical factor model consisting of 1 general and 4 specific factors fit to 48 psychiatric symptoms on which twin participants self-reported in 2005 and 1 general and 3 specific factors fit to 9 register-based psychiatric diagnoses assigned to sibling participants prior to 2005. Main Outcomes and Measures: Outcomes consisted of 7 register-based events occurring after 2005, including suicidal behavior, substance overdoses, and criminal suspicion or convictions (data available until the end of 2013), and prescription of antidepressants, antialcohol or antiopioid medication, antipsychotics, and stimulants (data available until the end of 2017). Results: The study included 32 328 twins (mean [SD] age, 34 [8] years; 16 076 [49.73%] male) and 1 942 106 siblings (mean [SD] age, 34 [7] years; 991 500 [51.05%] male). General psychopathology was significantly associated with all 7 outcomes within sibling pairs (mean within-pair odds ratio [OR], 2.28; 95% CI, 2.19-2.37) and dizygotic twin pairs (within-pairs OR, 1.65; 95% CI, 1.38-1.98) and with 3 outcomes within monozygotic twin pairs (mean within-pairs OR, 1.77; 95% CI, 1.35-2.36). Within sibling pairs, the specific internalizing factor was associated with antidepressant prescriptions (within-pairs OR, 1.65; 95% CI, 1.59-1.71), the specific substance misuse factor was associated prescription of antialcohol and antiopioid medication (within-pairs OR, 2.36; 95% CI, 2.20-2.54), and the specific psychotic factor was associated with antipsychotic medications (within-pairs OR, 1.61; 95% CI, 1.51-1.72). Similar results emerged within twin pairs. Conclusion and Relevance: In this cohort study, general psychopathology was significantly associated with all 7 outcomes within sibling and dizygotic twin pairs and 3 outcomes within monozygotic twin pairs at 10 years. Within twin and sibling pairs, the specific factors were primarily associated with related outcomes. Several of the associations in this cohort study could not be attributed to unmeasured confounds shared by family members, suggesting that interventions toward broad psychopathology dimensions might help reduce the risk of future clinically relevant events. [ABSTRACT FROM AUTHOR]

Background: Neurodevelopmental disorders (NDs) are associated with experiences of victimization, but mechanisms remain unclear. We explored sex differences and the role of familial factors and externalizing problems in the association between several NDs and violent victimization in adolescence and young adulthood. Methods: Individuals born in Sweden 1985–1997, residing in Sweden at their 15th birthday, were followed until date of violent victimization causing a hospital visit or death, death due to other causes, emigration, or December 31, 2013, whichever came first. The exposures were diagnoses of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID) and other NDs. We used three different Cox regression models: a crude model, a model adjusted for familial confounding using sibling-comparisons, and a model additionally adjusted for externalizing problems. Results: Among 1 344 944 individuals followed, on average, for 5 years, 74 487 were diagnosed with NDs and 37 765 had a hospital visit or died due to violence. ADHD was associated with an increased risk of violent victimization in males [hazard ratio (HR) 2.56; 95% confidence interval (CI) 2.43–2.70) and females (HR 5.39; 95% CI 4.97–5.85). ASD and ID were associated with an increased risk of violent victimization in females only. After adjusting for familial factors and externalizing problems, only ADHD was associated with violent victimization among males (HR 1.27; 95% CI 1.06–1.51) and females (HR 1.69; 95% CI 1.21–2.36). Conclusions: Females with NDs and males with ADHD are at greater risk of being victim of severe violence during adolescence and young adulthood. Relevant mechanisms include shared familial liability and externalizing problems. ADHD may be independently associated with violent victimization. [ABSTRACT FROM AUTHOR]

Sports participation, physical activity, and friendship quality are theorized to have protective effects on the developmental emergence of substance use and self-harm behavior in adolescence, but existing research has been mixed. This ambiguity could reflect, in part, the potential for confounding of observed associations by genetic and environmental factors, which previous research has been unable to rigorously rule out. We used data from the prospective, population-based Child and Adolescent Twin Study in Sweden (n = 18,234 born 1994–2001) and applied a co-twin control design to account for potential genetic and environmental confounding of sports participation, physical activity, and friendship quality (assessed at age 15) as presumed protective factors for adolescent substance use and self-harm behavior (assessed at age 18). While confidence intervals widened to include the null in numerous co-twin control analyses adjusting for childhood psychopathology, parent-reported sports participation and twin-reported positive friendship quality were associated with increased odds of alcohol problems and nicotine use. However, parent-reported sports participation, twin-reported physical activity, and twin-reported friendship quality were associated with decreased odds of self-harm behavior. The findings provide a more nuanced understanding of the risks and benefits of putative protective factors for risky behaviors that emerge during adolescence. [ABSTRACT FROM AUTHOR]

Background: Although polygenic risk scores (PRS) predict psychiatric problems, these associations might be attributable to indirect pathways including population stratification, assortative mating, or dynastic effects (mediation via parental environments). The goal of this study was to examine whether PRS‐psychiatric symptom associations were attributable to indirect versus direct pathways. Methods: The sample consisted of 3,907 dizygotic (DZ) twin pairs. In childhood, their parents rated them on 98 symptoms. In adolescence (n = 2,393 DZ pairs), both the parents and the twins rated themselves on 20 symptoms. We extracted one general and seven specific factors from the childhood data, and one general and three specific factors from the adolescent data. We then regressed each general factor model onto ten psychiatric PRS simultaneously. We first conducted the regressions between individuals (β) and then within DZ twin pairs (βw), which controls for indirect pathways. Results: In childhood, the PRS for ADHD predicted general psychopathology (β = 0.09, 95% CI: [0.06, 0.12]; βw = 0.07 [0.01, 0.12]). Furthermore, the PRS for ADHD predicted specific inattention (β = 0.04 [0.00, 0.08]; βw = 0.09 [0.01, 0.17]) and specific hyperactivity (β = 0.07 [0.04, 0.11]; βw = 0.09 [0.01, 0.16]); the PRS for schizophrenia predicted specific learning (β = 0.08 [0.03, 0.13]; βw = 0.19 [0.08, 0.30]) and specific inattention problems (β = 0.05 [0.01, 0.09]; βw = 0.10 [0.02, 0.19]); and the PRS for neuroticism predicted specific anxiety (β = 0.06 [0.02, 0.10]; βw = 0.06 [0.00, 0.12]). Overall, the PRS‐general factor associations were similar between individuals and within twin pairs, whereas the PRS‐specific factors associations amplified by 84% within pairs. Conclusions: This implies that PRS‐psychiatric symptom associations did not appear attributable to indirect pathways such as population stratification, assortative mating, or mediation via parental environments. Rather, genetics appeared to directly influence symptomatology. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between dispositional optimism and all-cause mortality after esophageal cancer surgery and whether pathological tumor stage and the COVID-19 pandemic modified this association. Methods: This nationwide, population-based prospective cohort study included 335 patients undergoing esophageal cancer surgery in Sweden between January 1, 2013, and December 31, 2019. Dispositional optimism was measured 1 year post-surgery using Life Orientation Test-Revised (LOT-R). A higher LOT-R sum score represents higher dispositional optimism. Mortality information was obtained from the Swedish Register of the Total Population. All patients were followed up until death or until December 31, 2020, whichever occurred first. Cox regression with adjustments for confounders was used. Results: The median follow-up was 20.8 months, during which 125 (37.3%) patients died. Among the included 335 patients, 219 (65.4%) patients had tumor pathologically staged Tis-II, and 300 (89.6%) patients entered the cohort before the COVID-19 pandemic. Both tumor stage and the COVID-19 pandemic were effect modifiers. For each unit increase in LOT-R sum score, the risk of all-cause mortality decreased by 11% (HR 0.89, 95% CI 0.81 to 0.98) among patients with tumor staged Tis-II before the COVID-19 pandemic. This association was non-significant in patients with tumor staged III–IV (HR 0.99, 95% CI 0.92 to 1.07) and during the COVID-19 pandemic (HR 1.08, 95% CI 0.94 to 1.25). Conclusion: Assessing dispositional optimism may help predict postoperative survival, especially for patients with early and intermediate esophageal cancer. Increasing dispositional optimism might be a potential intervention target to improve survival after esophageal cancer surgery. [ABSTRACT FROM AUTHOR]

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits. [ABSTRACT FROM AUTHOR]

Purpose: To examine the trajectory of psychological distress from 1 to 2 years after esophageal cancer surgery, and whether dispositional optimism could predict the risk of postoperative psychological distress.Methods: This Swedish nationwide longitudinal study included 192 patients who had survived for 1 year after esophageal cancer surgery. We measured dispositional optimism with the Life Orientation Test-Revised (LOT-R) 1 year post-surgery and psychological distress with the Hospital Anxiety and Depression Scale 1, 1.5, and 2 years post-surgery. Latent growth curve models were used to assess the trajectory of postoperative psychological distress and to examine the predictive validity of dispositional optimism.Results: One year after surgery, 11.5% (22 of 192) patients reported clinically significant psychological distress, and the proportion increased to 18.8% at 1.5 years and to 25.0% at 2 years post-surgery. Higher dispositional optimism predicted a lower probability of self-reported psychological distress at 1, 1.5, and 2 years after esophageal cancer surgery. For each point increase in the LOT-R sum score, the odds of psychological distress decreased by 44% (OR, 0.56; 95% CI, 0.40 to 0.79).Conclusion: The high prevalence and longitudinal increase of self-reported psychological distress after esophageal cancer surgery indicate the unmet demands for timely psychological screening and interventions. Measuring dispositional optimism may help identify patients at higher risk of developing psychological distress, thereby contributing to the prevention of postoperative psychological distress. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether higher dispositional optimism could predict better health-related quality of life (HRQL) after esophageal cancer surgery. Methods: This Swedish nationwide longitudinal study included 192 patients who underwent esophagectomy for cancer. The exposure was dispositional optimism measured by the Life Orientation Test-Revised (LOT-R) at 1 year post-surgery. Patients were categorized into four subgroups (very low, moderately low, moderately high, and very high dispositional optimism) based on the quartile of the LOT-R sum score. The outcome was HRQL assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Esophago-Gastric module 25 (QLQ-OG25) at 1, 1.5, and 2 years post-surgery. Linear mixed-effects models, adjusted for potential confounders, were used to examine the mean score difference (MSD) with 95% confidence interval of HRQL among the four patient subgroups. Results: Patients with very high dispositional optimism reported clinically relevantly better global quality of life, emotional function, and social function (MSD range 10–16) and less severe symptoms in pain, dyspnea, diarrhea, eating difficulty, anxiety, dry mouth, trouble with taste, worry about weight loss, and self-doubt about body image (MSD range − 9 to − 22) than patients with lower dispositional optimism. Patients with moderately high dispositional optimism reported clinically and statistically significantly better global quality of life (MSD 10) and less severe diarrhea (MSD − 9) than patients with lower dispositional optimism. Adjusted MSDs were constant over the three time points in all aspects except for eating difficulty. Conclusions: Measuring dispositional optimism could help identify patients at higher risk of poor HRQL recovery after esophageal cancer surgery. [ABSTRACT FROM AUTHOR]

Background: Research has demonstrated that individuals who identify as a sexual minority (e.g., gay/lesbian, bisexual) are at increased risk for suicidality‐related outcomes. However, previous research is primarily limited by the lack of adjustment for unmeasured (i.e., genetic and environmental) confounding factors and previous psychopathology. Methods: Using the Child and Adolescent Twin Study in Sweden, we employed a co‐twin control design to examine the extent to which the association between sexual orientation and adolescent suicide attempt and self‐harm (SA/SH) was independent of genetic and environmental factors shared by twins, as well as measured symptoms of childhood psychopathology. Results: Adolescents who identified as a sexual minority (i.e., gay/lesbian, bisexual, or other sexual orientation) were at two‐fold increased odds for SA/SH (OR, 2.01 [95% confidence interval, 1.63–2.49) compared to heterosexual adolescents. When adjusting for all genetic and shared environmental factors that make twins similar and for measured childhood psychopathology, the association remained positive but attenuated to OR, 1.55 (1.11–2.16). Conclusions: Identifying as a sexual minority was associated with approximately 50% increased odds of SA/SH in adolescence after adjusting for unmeasured genetic and environmental factors shared by twins and for childhood psychopathology. The results support that environmental factors specifically associated with identifying as a sexual minority likely increase risk for SA/SH. Our findings highlight the need to monitor suicidality risk among this group. [ABSTRACT FROM AUTHOR]

Background: Although attention-deficit hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the latest diagnostic manuals, it shows phenotypic and genetic associations of similar magnitudes across neurodevelopmental, externalising and internalising disorders.Aims: To investigate if ADHD is aetiologically more closely related to neurodevelopmental than externalising or internalising disorder clusters, after accounting for a general psychopathology factor.Method: Full and maternal half-sibling pairs (N = 774 416), born between 1980 and 1995, were identified from the Swedish Medical Birth and Multi-Generation Registers, and ICD diagnoses were obtained from the Swedish National Patient Register. A higher-order confirmatory factor analytic model was fitted to examine associations between ADHD and a general psychopathology factor, as well as a neurodevelopmental, externalising and internalising subfactor. Quantitative genetic modelling was performed to estimate the extent to which genetic, shared and non-shared environmental effects influenced the associations with ADHD.Results: ADHD was significantly and strongly associated with all three factors (r = 0.67-0.75). However, after controlling for a general psychopathology factor, only the association between ADHD and the neurodevelopmental-specific factor remained moderately strong (r = 0.43, 95% CI = 0.42-0.45) and was almost entirely influenced by genetic effects. In contrast, the association between ADHD and the externalising-specific factor was smaller (r = 0.25, 95% CI = 0.24-0.27), and largely influenced by non-shared environmental effects. There remained no internalising-specific factor after accounting for a general factor.Conclusions: Findings suggest that ADHD comorbidity is largely explained by genetically influenced general psychopathology, but the strong link between ADHD and other neurodevelopmental disorders is also substantially driven by unique genetic influences. [ABSTRACT FROM AUTHOR]

Background: Top‐down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal‐directed action in everyday life. In this twin study, we examined the relation between performance on a response inhibition eye‐tracking paradigm and parent‐rated ADHD traits in a population‐based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors. Methods: A total of 640 twins (320 pairs, 50% monozygotic) aged 9–14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed‐effects models and genetic and environmental influences with multivariate twin models. Results: Premature anticipatory eye movements were positively associated with inattentive traits (β =.17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2 = 0.40, 95% CI: 0.22, 0.56; h2 = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r =.19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits. Conclusions: This study indicates that there is a specific, genetically influenced, relation between top‐down eye movement control and the inattentive traits typical of ADHD. [ABSTRACT FROM AUTHOR]

The beneficial effects of protons are primarily based on reduction of low to intermediate radiation dose bath to normal tissue surrounding the radiotherapy target volume. Despite promise for reduced long-term toxicity, the percentage of cancer patients treated with proton therapy remains low. This is probably caused by technical improvements in planning and delivery of photon therapy, and by high cost, low availability and lack of high-level evidence on proton therapy. A number of proton treatment facilities are under construction or have recently opened; there are now two operational Scandinavian proton centres and two more are under construction, thereby eliminating the availability hurdle. Even with the advantageous physical properties of protons, there is still substantial ambiguity and no established criteria related to which patients should receive proton therapy. This topic was discussed in a session at the Nordic Collaborative Workshop on Particle Therapy, held in Uppsala 14–15 November 2019. This paper resumes the Nordic-Baltic perspective on proton therapy indications and discusses strategies to identify patients for proton therapy. As for indications, neoplastic entities, target volume localisation, size, internal motion, age, second cancer predisposition, dose escalation and treatment plan comparison based on the as low as reasonably achievable (ALARA) principle or normal tissue complication probability (NTCP) models were discussed. Importantly, the patient selection process should be integrated into the radiotherapy community and emphasis on collaboration across medical specialties, involvement of key decision makers and knowledge dissemination in general are important factors. An active Nordic-Baltic proton therapy organisation would also serve this purpose. [ABSTRACT FROM AUTHOR]

Background: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems. Methods: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow‐up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations. Results: On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (βboys =.24, standard error, SE = 0.03; βgirls =.17, SE = 0.03), above and beyond its association with the externalizing (βboys = 0.21, SE = 0.04; βgirls = 0.17, SE = 0.05) and general factors (βboys = 0.45, SE = 0.03; βgirls = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors. Conclusions: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels. [ABSTRACT FROM AUTHOR]

Visual disengagement has been hypothesized as an endophenotype for autism. In this study we used twin modelling to assess the role of genetics in basic measures of visual disengagement, and tested their putative association to autistic traits in the general population. We used the Gap Overlap task in a sample of 492 twins. Results showed that most of the covariance among eye movement latencies across conditions was shared and primarily genetic. Further, there were unique genetic contributions to the Gap condition, but not to the Overlap condition—i.e. the one theorized to capture visual disengagement. We found no phenotypic association between autistic traits and disengagement, thus not supporting the hypothesis of visual disengagement as an endophenotype for autistic traits. [ABSTRACT FROM AUTHOR]

Background: Traits of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are strongly associated in children and adolescents, largely due to genetic factors. Less is known about the phenotypic and aetiological overlap between ADHD and ASD traits in adults. Methods: We studied 6866 individuals aged 20–28 years from the Swedish Study of Young Adult Twins. Inattention (IA) and hyperactivity/impulsivity (HI) were assessed using the WHO Adult ADHD Self-Report Scale-V1.1. Repetitive and restricted behaviours (RRB) and social interaction and communication (SIC) were assessed using the Autism-Tics, ADHD, and other Comorbidities inventory. We used structural equation modelling to decompose covariance between these ADHD and ASD trait dimensions into genetic and shared/non-shared environmental components. Results: At the phenotypic level, IA was similarly correlated with RRB (r = 0.33; 95% Confidence Interval (CI) 0.31–0.36) and with SIC (r = 0.32; 95% CI 0.29–0.34), whereas HI was more strongly associated with RRB (r = 0.38; 95% CI 0.35–0.40) than with SIC (r = 0.24; 95% CI 0.21–0.26). Genetic and non-shared environmental effects accounted for similar proportions of the phenotypic correlations, whereas shared environmental effects were of minimal importance. The highest genetic correlation was between HI and RRB (r = 0.56; 95% 0.46–0.65), and the lowest was between HI and SIC (r = 0.33; 95% CI 0.23–0.43). Conclusions: We found evidence for dimension-specific phenotypic and aetiological overlap between ADHD and ASD traits in adults. Future studies investigating mechanisms underlying comorbidity between ADHD and ASD may benefit from exploring several symptom-dimensions, rather than considering only broad diagnostic categories. [ABSTRACT FROM AUTHOR]

Importance: It is unclear if the associations between fetal growth and later mental health conditions remain after controlling for familial factors and psychiatric comorbidity.Objective: To examine the associations between fetal growth and general and specific mental health conditions, controlling for familial factors.Design, Setting, and Participants: This register-based study conducted in Sweden analyzed 546 894 pairs of full siblings born between January 1, 1973, and December 31, 1998. Sibling pairs were followed up through December 31, 2013. First, population-based and within-sibling pair associations (which controlled for time-invariant familial confounders) between fetal growth and the outcomes were estimated. Second, exploratory factor analysis was applied to the outcomes to derive 1 general factor and 4 specific and independent factors. Third, the general and specific factors were regressed on fetal growth. Statistical analysis was performed from March 27, 2017, to October 27, 2018.Main Outcome and Measures: The outcomes were 11 psychiatric diagnoses (depression, anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, alcohol abuse, drug use, attention-deficit/hyperactivity disorder, autism, schizophrenia, and schizoaffective disorder) and court convictions of violent crimes. Birth weight (in kilograms) statistically adjusted for gestational age was the exposure.Results: The mean (SD) age of the 1 093 788 participants was 27.2 (6.8) years (range, 15.1-40.9 years) and 51.5% were male. Nine outcomes were significantly associated with birth weight in the population at large: depression (odds ratio [OR], 0.96; 95% CI, 0.95-0.98), anxiety (OR, 0.94; 95% CI, 0.92-0.95), posttraumatic stress disorder (OR, 0.91; 95% CI, 0.89-0.93), bipolar disorder (OR, 0.94; 95% CI, 0.89-1.00), alcohol abuse (OR, 0.89; 95% CI, 0.87-0.91), drug use (OR, 0.83; 95% CI, 0.80-0.85), violent crimes (OR, 0.85; 95% CI, 0.83-0.86), attention-deficit/hyperactivity disorder (OR, 0.88; 95% CI, 0.86-0.90), and autism (OR, 0.95; 95% CI, 0.92-0.97). Only depression (OR, 0.95; 95% CI 0.92-0.98), obsessive-compulsive disorder (OR, 0.93; 95% CI, 0.87-0.99), attention-deficit/hyperactivity disorder (OR, 0.86; 95% CI, 0.82-0.89), and autism (OR, 0.72; 95% CI, 0.69-0.76) remained significantly associated within sibling pairs. An exploratory factor analysis indicated that 1 general and 4 specific factors (capturing anxiety, externalizing, neurodevelopmental, and psychotic conditions) fit the outcomes well. Across almost all sensitivity analyses, an increase in birth weight by 1 kg significantly reduced the general (β, -0.047; 95% CI, -0.071 to -0.023) and the specific neurodevelopmental factors (β, -0.159; 95% CI, -0.190 to -0.128) within sibling pairs.Conclusions and Relevance: Controlling for familial confounders, reduced fetal growth was associated with a small but significant increase in the general factor of psychopathology and a moderate increase in a specific neurodevelopmental factor. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD), Attention‐deficit/Hyperactivity disorder (ADHD), and other related neurodevelopmental disorders (NDDs) have, in some previous studies, been shown to increase the risk of being sexually victimized. However, no studies have examined whether the association is driven by a general NDD phenotype versus specific diagnoses, nor the etiology of the association. Method: Using a genetically informative, prospective design, we examined the association between ASD and ADHD in childhood and coercive sexual victimization up to age 18. A total of 4,500 children participating in the Child and Adolescent Twin Study in Sweden (CATSS) were rated by their parents on NDDs at age 9 or 12 years, and self‐reported at age 18 on lifetime experiences of coercive sexual touching and/or coercive sex. First, we regressed sexual victimization on the NDDs. Second, we regressed sexual victimization on general and specific NDD symptoms identified via a bifactor model. Third, we decomposed the observed associations into genetic and environmental parts. Results: In females, ASD was associated with an almost threefolded increased risk of coercive sexual victimization, and ADHD with a doubled risk. In males, the risk associated with ASD and ADHD was of the same magnitude but not significant. When controlling for overall NDD symptom load ASD or ADHD, no longer uniquely predicted coercive sexual victimization. The association between the NDD general factor and coercive sexual victimization was due to shared genetics. Conclusions: General NDD symptom load, rather than specific ASD or ADHD symptoms, seems to be a moderate vulnerability factor for coercive sexual victimization. We speculate that an evocative gene–environment correlation might account for this observation, such that sexual perpetrators actively target NDD individuals. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) has been associated with gastrointestinal (GI) problems, but the nature of this association is unclear. Parents to siblings, concordant or discordant for ASD ( N = 217), participated in a web survey covering mother's weight gain during pregnancy, maternal viral/bacterial infection and use of antibiotics, duration of breastfeeding, mode of delivery, birth weight and child GI problems. ASD was associated with GI problems and perinatal environmental risk, based on a summation of maternal infection and antibiotic use during pregnancy and/or the breastfeeding period. The association between GI problems and ASD remained within the sibling pairs ( β = 1.23; p < .001) in the adjusted model. Our results indicate non-shared environmental effects on the ASD/GI association, but none of the factors examined explained the link. [ABSTRACT FROM AUTHOR]

Bully victimization is a common problem among children with neurodevelopmental disorders, including attention deficit/hyperactivity disorder and autism spectrum disorder. Previous research was mostly cross-sectional and seldom accounted for co-morbid psychopathology, which makes it difficult to draw conclusions about causality and specificity of any association. Using a genetically informative prospective design, we investigated the association between various neurodevelopmental problems (NDPs) in childhood and bully victimization in adolescence, and the relative contributions of genetic and environmental factors to this association. We obtained parent-reports of NDPs at age 9/12 years and self-reported bully victimization at age 15 for 3,921 children participating in the The Child and Adolescent Twin Study in Sweden (CATSS). Structural equation modelling was used to control for NDP co-morbidity and bully victimization at baseline. Cholesky decomposition was used to analyse genetic and environmental contributions to observed associations. Because most of the NDPs were associated to later bully victimization, a common effect of all NDPs was summarized into a general NDP factor. Controlling for this general factor, only problems with social interaction and motor control uniquely predicted subsequent bully victimization in girls. General and unique associations were influenced by both genetic and unique environmental factors. NDPs in general and social interaction and motor problems in particular predicted later bully victimization. The longitudinal design and twin analyses indicated that these associations might be causal. Knowledge of these vulnerabilities may be important when designing risk assessment and prevention strategies. [ABSTRACT FROM AUTHOR]

Background Studies have found an association between low birth weight and ADHD, but the nature of this relation is unclear. First, it is uncertain whether birth weight is associated with both of the ADHD dimensions, inattentiveness and hyperactivity-impulsivity. Second, it remains uncertain whether the association between birth weight and ADHD symptom severity is confounded by familial factors. Method Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM- IV inattentive and hyperactive-impulsive ADHD symptoms by the Autism - Tics, AD/ HD and other Comorbidities (A- TAC) inventory ( N = 21,775 twins). Birth weight was collected prospectively through the Medical Birth Registry. We used a within-twin pair design to control for genetic and shared environmental factors. Results Reduced birth weight was significantly associated with a mean increase in total ADHD (β = −.42; 95% CI: −.53, −.30), inattentive (β = −.26; 95% CI: −.33, −.19), and hyperactive-impulsive (β = −.16; 95% CI: −.22, −.10) symptom severity. These results imply that a change of one kilogram of birth weight corresponded to parents rating their child nearly one unit higher (going from 'no' to 'yes, to some extent' on a given symptom) on the total ADHD scale. These associations remained within pairs of MZ and DZ twins, and were also present when restricting the analyses to full term births. Conclusions There is an independent association between low birth weight and all forms of ADHD symptoms, even after controlling for all environmental and genetic confounds shared within twin pairs. These results indicate that fetal growth restriction (as reflected in birth weight differences within twin pairs) and/or the environmental factors which influence it is in the casual pathway leading to ADHD. [ABSTRACT FROM AUTHOR]

Restriction enzymes that recognize specific sequences but cleave unknown sequence outside the recognition site are extensively utilized tools in molecular biology. Despite this, systematic functional categorization of cleavage performance has largely been lacking. We established a simple and automatable model system to assay cleavage distance variation (termed slippage) and the sequence dependence thereof. We coupled this to massively parallel sequencing in order to provide sensitive and accurate measurement. With this system 14 enzymes were assayed (AcuI, BbvI, BpmI, BpuEI, BseRI, BsgI, Eco57I, Eco57MI, EcoP15I, FauI, FokI, GsuI, MmeI and SmuI). We report significant variation of slippage ranging from 1–54%, variations in sequence context dependence, as well as variation between isoschizomers. We believe this largely overlooked property of enzymes with shifted cleavage would benefit from further large scale classification and engineering efforts seeking to improve performance. The gained insights of in-vitro performance may also aid the in-vivo understanding of these enzymes. [ABSTRACT FROM AUTHOR]

Background Autistic-like traits (ALTs) are continuously distributed in the general population, with the autism spectrum disorder (ASD) at the upper extreme end. A genetic overlap has been shown between ALTs and ASD, indicating that common variation in ASD candidate genes may also influence ALTs. In our study, we have investigated the SNP rs4307059 that has been associated with both ALTs and ASD. In addition, we genotyped polymorphisms in a selection of genes involved in synaptic functioning, that is, SHANK3, RELN, and CNTNAP2, which repeatedly have been associated with ASD. The possible associations of these polymorphisms with ALTs, as well as genetic factors for neurodevelopmental problems (NDPs), were investigated in a large cohort from the general population: The Child and Adolescent Twin Study in Sweden. For analyses of ALTs and NDPs, 12,319 subjects (including 2,268 monozygotic (MZ) and 3,805 dizygotic (DZ) twin pairs) and 8,671 subjects (including 2,243 MZ and 2,044 DZ twin pairs), respectively, were included in the analyses. Findings We could not replicate the previous association between rs4307059 and social communication impairment. Moreover, common variations in CNTNAP2 (rs7794745 and rs2710102), RELN (rs362691), and SHANK3 (rs9616915) were not significantly associated with ALTs in our study. Conclusions Our results do not suggest that the investigated genes, which previously has been found associated with ASD diagnosis, have any major influence on ALTs in children from the general population. [ABSTRACT FROM AUTHOR]

Although simple structure is often used as a theoretical guideline for rotation of exploratory factor structures, its empirical foundation is sometimes not investigated. We examined the degree of simple structure in 2 self-report inventories advocated for the description of personality pathology. The multivariate complexity of the inventories was compared against simulated factorial solutions with increasing degrees of simple structure. Results revealed a high degree of complexity in both inventories, regardless of whether focusing on a few broad or many narrow factors and whether items or scales were analyzed. It is concluded that Thurstone's (1934) simple structure criteria are rarely fulfilled in multivariate personality pathology solutions, and, therefore, that alternate rotations represent equally justifiable ways to operationalize the space. Furthermore, using iterative test development to impose simple structure where none originally existed increased standard errors around the factor scores in the interstitial areas between imposed simple structure dimensions. In both simulated and real data, multidimensional item response theory test information functions based on complex solutions demonstrated that test information was uniformly distributed across the space. In contrast, in simple structure solutions, information was weak in areas of the space where nonconforming items had been removed. Implications are discussed. [ABSTRACT FROM PUBLISHER]

Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized. [ABSTRACT FROM AUTHOR]

We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level. [ABSTRACT FROM AUTHOR]

Background Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome. Method Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems. Results One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively. Conclusion One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems. [ABSTRACT FROM AUTHOR]

Here we present a novel approach entitled Magnetic Forced Hybridization (MFH) that provides the means for efficient and direct hybridization of target nucleic acids to complementary probes immobilized on a glass surface in less than 15 seconds at ambient temperature. In addition, detection is carried out instantly since the beads become visible on the surface. The concept of MFH was tested for quality control of array manufacturing, and was combined with a multiplex competitive hybridization (MUCH) approach for typing of Human Papilloma Virus (HPV). Magnetic Forced Hybridization of bead-DNA constructs to a surface achieves a significant reduction in diagnostic testing time. In addition, readout of results by visual inspection of the unassisted eye eliminates the need for additional expensive instrumentation. The method uses the same set of beads throughout the whole process of manipulating and washing DNA constructs prior to detection, as in the actual detection step itself. [ABSTRACT FROM AUTHOR]

According to the proposal of the general factor of personality (GFP), socially desirable personality traits have been selected for throughout evolution because they increase fitness. However, it remains unknown whether people high on this factor actually behave in socially desirable ways or whether they simply endorse traits of positive valence. We separated these two sources of variance by having 619 participants respond to 120 personality adjectives organised into 30 quadruples balanced for content and valence (e.g. unambitious, easy-going, driven and workaholic tapped the trait achievement-striving). An exploratory six-factor solution fit well, and the factors resembled the Big Five. We subsequently extracted a higher-order factor from this solution, which appeared similar to the GFP. A Schmid-Leiman transformation of the higher-order factor, however, revealed that it clustered items of similar valence but opposite content (e.g. at the negative pole, unambitious and workaholic), rendering it an implausible description of evolved adaptive behaviour. Isolating this evaluative factor using exploratory structural equation modelling generated factors consisting of items of similar descriptive content but different valence (e.g. driven and workaholic), and the correlations among these factors were of small magnitude, indicating that the putative GFP capitalises primarily on evaluative rather than descriptive variance. Implications are discussed. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Massively parallel sequencing systems continue to improve on data output, while leaving labor-intensive library preparations a potential bottleneck. Efforts are currently under way to relieve the crucial and time-consuming work to prepare DNA for high-throughput sequencing. Methodology/Principal Findings: In this study, we demonstrate an automated parallel library preparation protocol using generic carboxylic acid-coated superparamagnetic beads and polyethylene glycol precipitation as a reproducible and flexible method for DNA fragment length separation. With this approach the library preparation for DNA sequencing can easily be adjusted to a desired fragment length. The automated protocol, here demonstrated using the GS FLX Titanium instrument, was compared to the standard manual library preparation, showing higher yield, throughput and great reproducibility. In addition, 12 libraries were prepared and uniquely tagged in parallel, and the distribution of sequence reads between these indexed samples could be improved using quantitative PCR-assisted pooling. Conclusions/Significance: We present a novel automated procedure that makes it possible to prepare 36 indexed libraries per person and day, which can be increased to up to 96 libraries processed simultaneously. The yield, speed and robust performance of the protocol constitute a substantial improvement to present manual methods, without the need of extensive equipment investments. The described procedure enables a considerable efficiency increase for small to midsize sequencing centers. [ABSTRACT FROM AUTHOR]

Here we present an approach for allelotyping combining the multiplexing features of the trinucleotide threading (TnT) method with pooling of genomic DNA and massively parallel pyrosequencing, enabling reliable allele frequency estimation in large cohorts. The approach offers several benefits as compared to array-based methods and allows undertaking highly complex studies without compromising accuracy, while keeping the workload to a minimum. This proof-of-concept study involves formation of trinucleotide threads, targeting a total of 147 single-nucleotide polymorphisms (SNPs) related to obesity and cancer, for multiplex amplification and allele extraction from a pool of 462 genomes, followed by massively parallel pyrosequencing. Approximately 177k reads were approved, identified, and assigned to SNP-carrying threads rendering representative allele frequencies in the cohort. Hum Mutat 29(2), 323-329, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites. [ABSTRACT FROM AUTHOR]

Here we describe the novel Sequencing Bead Array (SBA), a complete assay for molecular diagnostics and typing applications. SBA is a digital suspension array using Next-Generation Sequencing (NGS), to replace conventional optical readout platforms. The technology allows for reducing the number of instruments required in a laboratory setting, where the same NGS instrument could be employed from whole-genome and targeted sequencing to SBA broad-range biomarker detection and genotyping. As proof-of-concept, a model assay was designed that could distinguish ten Human Papillomavirus (HPV) genotypes associated with cervical cancer progression. SBA was used to genotype 20 cervical tumor samples and, when compared with amplicon pyrosequencing, was able to detect two additional co-infections due to increased sensitivity. We also introduce in-house software Sphix, enabling easy accessibility and interpretation of results. The technology offers a multi-parallel, rapid, robust, and scalable system that is readily adaptable for a multitude of microarray diagnostic and typing applications, e.g. genetic signatures, single nucleotide polymorphisms (SNPs), structural variations, and immunoassays. SBA has the potential to dramatically change the way we perform probe-based applications, and allow for a smooth transition towards the technology offered by genomic sequencing. [ABSTRACT FROM AUTHOR]