Publications by authors named "Sven Sandin"

142 Publications

Meta-analysis for individual participant data with a continuous exposure: a case study.

J Clin Epidemiol 2021 09 3. Epub 2021 Sep 3.

University of Queensland, School of Public Health, Faculty of Medicine, Queensland, Australia. Electronic address:

Objective: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible.

Study Design And Setting: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods.

Results: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results.

Conclusion: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment.
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http://dx.doi.org/10.1016/j.jclinepi.2021.08.033DOI Listing
September 2021

Gestational diabetes and risk of breast cancer before age 55 years.

Int J Epidemiol 2021 Aug 29. Epub 2021 Aug 29.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting.

Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors.

Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women.

Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM.
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http://dx.doi.org/10.1093/ije/dyab165DOI Listing
August 2021

Optimal interpregnancy interval in autism spectrum disorder: A multi-national study of a modifiable risk factor.

Autism Res 2021 Aug 23. Epub 2021 Aug 23.

National Centre for Register-based Research, Department of Economics and Business, Aarhus University, Aarhus, Denmark.

It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35 months for all countries combined, and at 30, 33, and 39 months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60 months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35 months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39 months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35 months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing.
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http://dx.doi.org/10.1002/aur.2599DOI Listing
August 2021

Lifestyle changes and risk of cancer: experience from the Swedish women's lifestyle and health cohort study.

Acta Oncol 2021 Jul 14;60(7):827-834. Epub 2021 May 14.

International Agency for Research on Cancer, Lyon, France.

Background: The impact of lifestyle changes on cancer risk is yet to be elucidated. We investigated this issue in the Swedish Women's Lifestyle and Health Cohort Study.

Material And Methods: We measured changes by comparing two questionnaires, filled in 1991/92 and 2003. We followed women for cancer from 2003 until 2012. We used Cox regression models to assess the effect of changes in smoking, alcohol consumption, body mass index (BMI), physical activity and a lifestyle score on the risk of lifestyle-related cancer. One point was added to the lifestyle score for each of these: non-smoking, alcohol consumption ≤12 grams/day, BMI <25 kg/m and high level of physical activity.

Results: We included 29,930 women. From 1991/92 to 2003, median age changed from 40.0 to 51.7 years, alcohol consumption from 2.5 to 4.7 grams/day, BMI from 22.7 to 24.5 kg/m, proportion of current smokers from 31.0 to 20.6% and women reporting high physical activity from 27.2 to 37.0%. Women who quit smoking had lower risk of smoking-related cancers compared to women who continued (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.55-1.00). Women who reduced their weight by more than 5%, compared to women with stable weight, had lower risk of breast cancer (HR 0.49, 95% CI 0.31-0.78). Among women with score of 0-2 in 1992/93, those who improved to 3-4 had lower risk of lifestyle-related cancers compared to women who did not (HR 0.81, 95% CI 0.66-0.99).

Conclusions: Healthy lifestyle changes, particularly smoking cessation and weight reduction, were associated with a decreased risk of cancer.
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http://dx.doi.org/10.1080/0284186X.2021.1919756DOI Listing
July 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 2021

Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study.

Psychol Med 2021 Mar 26:1-9. Epub 2021 Mar 26.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring.

Methods: This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period).

Results: The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11].

Conclusions: Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.
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http://dx.doi.org/10.1017/S0033291721001021DOI Listing
March 2021

Mortality Among Young Adults Born Preterm and Early Term in 4 Nordic Nations.

JAMA Netw Open 2021 01 4;4(1):e2032779. Epub 2021 Jan 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Importance: Adverse long-term outcomes in individuals born before full gestation are not confined to individuals born at extreme gestational ages. Little is known regarding mortality patterns among individuals born in the weeks close to ideal gestation, and the exact causes are not well understood; both of these are crucial for public health, with the potential for modification of risk.

Objective: To examine the risk of all-cause and noncommunicable diseases (NCD) deaths among young adults born preterm and early term.

Design, Setting, And Participants: This multinational population-based cohort study used nationwide birth cohorts from Norway, Sweden, Denmark, and Finland for individuals born between 1967 and 2002. Individuals identified at birth who had not died or emigrated were followed up for mortality from age 15 years to 2017. Analyses were performed from June 2019 to May 2020.

Exposures: Categories of gestational age (ie, moderate preterm birth and earlier [23-33 weeks], late preterm [34-36 weeks], early term [37-38 weeks], full term [39-41 weeks] and post term [42-44 weeks]).

Main Outcomes And Measures: All-cause mortality and cause-specific mortality from NCD, defined as cancer, diabetes, chronic lung disease, and cardiovascular disease (CVD).

Results: A total of 6 263 286 individuals were followed up for mortality from age 15 years. Overall, 339 403 (5.4%) were born preterm, and 3 049 100 (48.7%) were women. Compared with full-term birth, the adjusted hazard ratios (aHRs) for all-cause mortality were 1.44 (95% CI, 1.34-1.55) for moderate preterm birth and earlier; 1.23 (95% CI, 1.18-1.29) for late preterm birth; and 1.12 (95% CI, 1.09-1.15) for early-term birth. The association between gestational age and all-cause mortality were stronger in women than in men (P for interaction = .03). Preterm birth was associated with 2-fold increased risks of death from CVD (aHR, 1.89; 95% CI, 1.45-2.47), diabetes (aHR, 1.98; 95% CI, 1.44-2.73), and chronic lung disease (aHR, 2.28; 95% CI, 1.36-3.82). The main associations were replicated across countries and could not be explained by familial or individual confounding factors.

Conclusions And Relevance: The findings of this study strengthen the evidence of increased risk of death from NCDs in young adults born preterm. Importantly, the increased death risk was found across gestational ages up to the ideal term date and includes the much larger group with early-term birth. Excess mortality associated with shorter gestational age was most pronounced for CVDs, chronic lung disease, and diabetes.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.32779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794670PMC
January 2021

Medications for attention-deficit/hyperactivity disorder in individuals with or without coexisting autism spectrum disorder: analysis of data from the Swedish prescribed drug register.

J Neurodev Disord 2020 12 23;12(1):44. Epub 2020 Dec 23.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77, Stockholm, Sweden.

Background: Clinical studies found that medication for attention-deficit/hyperactivity disorder (ADHD) is effective in coexisting autism spectrum disorder (ASD), but current research is based on small clinical studies mainly performed on children or adolescents. We here use register data to examine if individuals with ADHD and coexisting ASD present differences in the prescribing patterns of ADHD medication when compared to individuals with pure ADHD.

Methods: Data with information on filled prescriptions and diagnoses was retrieved from the Swedish Prescribed Drug Register and the National Patient Register. We identified 34,374 individuals with pure ADHD and 5012 individuals with ADHD and coexisting ASD, aged between 3 and 80 years. The first treatment episode with ADHD medications (≥ 2 filled prescriptions within 90 days) and daily doses of methylphenidate during a 3-year period was measured. Odds ratios (ORs) were calculated for the likelihood of being prescribed ADHD medication in individuals with and without ASD and Wilcoxon rank-sum test was used to compare group differences in dose per day.

Results: Individuals with ADHD and coexisting ASD were less likely to start continuous treatment with ADHD medication (ADHD 80.5%; ADHD with ASD 76.2%; OR, 0.80; 95% confidence interval, 0.75-0.86), were less likely to be prescribed methylphenidate, and were more commonly prescribed second line treatments such as dexamphetamine, amphetamine, or modafinil. No group difference was observed for atomoxetine. In adults with ADHD and coexisting ASD, methylphenidate was prescribed in lower daily doses over three years as compared to individuals with pure ADHD.

Conclusions: The findings indicate that there are differences in the medical treatment of individuals with or without ASD. If these differences are due to different medication responses in ASD or due to other factors such as clinicians' perceptions of medication effects in patients with ASD, needs to be further studied.
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http://dx.doi.org/10.1186/s11689-020-09352-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758935PMC
December 2020

The Familial Risk of Autism Spectrum Disorder with and without Intellectual Disability.

Autism Res 2020 12 26;13(12):2242-2250. Epub 2020 Oct 26.

Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, Pennsylvania, USA.

Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies.
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http://dx.doi.org/10.1002/aur.2417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821228PMC
December 2020

Mediterranean Dietary Pattern at Middle Age and Risk of Parkinson's Disease: A Swedish Cohort Study.

Mov Disord 2021 01 20;36(1):255-260. Epub 2020 Oct 20.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: The Mediterranean diet has been proposed to protect against neurodegeneration.

Objectives: The aim of this study was to assess the association of adherence to Mediterranean dietary pattern (MDP) at middle age with risk for Parkinson's disease (PD) later in life.

Method: In a population-based cohort of >47,000 Swedish women, information on diet was collected through a food frequency questionnaire during 1991-1992, from which adherence to MDP was calculated. We also collected detailed information on potential confounders. Clinical diagnosis of PD was ascertained from the Swedish National Patient Register through 2012.

Results: We observed an inverse association between adherence to MDP and PD, multivariable hazard ratio of 0.54 (95% confidence interval: 0.30-0.98), comparing high with low adherence. The association was noted primarily from age 65 years onward. One unit increase in the adherence score was associated with a 29% lower risk for PD at age ≥ 65 years (95% confidence interval: 0.57-0.89).

Conclusion: Higher adherence to a Mediterranean diet at middle age was associated with lower risk for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894345PMC
January 2021

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

J Am Acad Child Adolesc Psychiatry 2021 05 1;60(5):623-636. Epub 2020 Oct 1.

Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Objective: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.

Method: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.

Results: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).

Conclusion: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.
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http://dx.doi.org/10.1016/j.jaac.2020.08.443DOI Listing
May 2021

Gestational age and the risk of autism spectrum disorder in Sweden, Finland, and Norway: A cohort study.

PLoS Med 2020 09 22;17(9):e1003207. Epub 2020 Sep 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Introduction: The complex etiology of autism spectrum disorder (ASD) is still unresolved. Preterm birth (<37 weeks of gestation) and its complications are the leading cause of death of babies in the world, and those who survive often have long-term health problems. Length of gestation, including preterm birth, has been linked to ASD risk, but robust estimates for the whole range of gestational ages (GAs) are lacking. The primary objective of this study was to provide a detailed and robust description of ASD risk across the entire range of GAs while adjusting for sex and size for GA.

Methods And Findings: Our study had a multinational cohort design, using population-based data from medical registries in three Nordic countries: Sweden, Finland, and Norway. GA was estimated in whole weeks based on ultrasound. Children were prospectively followed from birth for clinical diagnosis of ASD. Relative risk (RR) of ASD was estimated using log-binomial regression. Analyses were also stratified by sex and by size for GA. The study included 3,526,174 singletons born 1995 to 2015, including 50,816 (1.44%) individuals with ASD. In the whole cohort, 165,845 (4.7%) were born preterm. RR of ASD increased by GA, from 40 to 24 weeks and from 40 to 44 weeks of gestation. The RR of ASD in children born in weeks 22-31, 32-36, and 43-44 compared to weeks 37-42 were estimated at 2.31 (95% confidence interval [CI] 2.15-2.48; 1.67% vs 0.83%; p-value < 0.001), 1.35 (95% CI 1.30-1.40; 1.08% vs 0.83%; p-value < 0.001), and 1.37 (95% CI 1.21-1.54; 1.74% vs 0.83%; p-value < 0.001), respectively. The main limitation of this study is the lack of data on potential causes of pre- or postterm birth. Also, the possibility of residual confounding should be considered.

Conclusion: In the current study, we observed that the RR of ASD increased weekly as the date of delivery diverged from 40 weeks, both pre- and postterm, independently of sex and size for GA. Given the unknown etiology of ASD and the lifelong consequences of the disorder, identifying groups of increased risk associated with a potentially modifiable risk factor is important.

Author Summary:
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http://dx.doi.org/10.1371/journal.pmed.1003207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508401PMC
September 2020

Healthcare-Associated Legionnaires' Disease, Europe, 2008-2017.

Emerg Infect Dis 2020 10;26(10):2309-2318

Healthcare-associated Legionnaires' disease (HCA LD) can cause nosocomial outbreaks with high death rates. We compared community-acquired LD cases with HCA LD cases in Europe during 2008-2017 using data from The European Surveillance System. A total of 29 countries reported 40,411 community-acquired and 4,315 HCA LD cases. Of the HCA LD cases, 2,937 (68.1%) were hospital-acquired and 1,378 (31.9%) were linked to other healthcare facilities. The odds of having HCA LD were higher for women, children and persons <20 years of age, and persons >60 years of age. Out of the cases caused by Legionella pneumophila with a known serotype, community-acquired LD was more likely to be caused by L. pneumophila serogroup 1 (92.3%) than was HCA LD (85.1%). HCA LD patients were more likely to die. HCA LD is associated with specific patient demographics, causative strains, and outcomes. Healthcare facilities should consider these characteristics when designing HCA LD prevention strategies.
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http://dx.doi.org/10.3201/eid2610.181889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510712PMC
October 2020

Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease: A Pooled Analysis of Individual Patient Data From 12 Studies.

JAMA Cardiol 2020 Dec;5(12):1410-1418

School of Public Health, The University of Queensland, Brisbane, Australia.

Importance: Early menarche and early menopause are associated with increased risk of cardiovascular disease (CVD) in midlife, but little is known about the association between reproductive life span and the risk of CVD.

Objective: To investigate the association between the length of reproductive life span and risk of incident CVD events, while also considering the timing of menarche and menopause.

Design, Setting, And Participants: Individual-level data were pooled from 12 studies participating in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events consortium. Women provided complete information on the timing of menarche and menopause, nonfatal CVD events, and covariates. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs, adjusted for covariates. The association between reproductive life span and CVD was adjusted for age at menarche and age at menopause separately. Analysis began March 2018 and ended December 2019.

Exposures: Reproductive life span was calculated by subtracting age at menarche from age at menopause and categorized as younger than 30, 30 to 32, 33 to 35, 36 to 38 (reference group), 39 to 41, 42 to 44, and 45 years or older.

Main Outcomes And Measures: First nonfatal CVD event, including coronary heart disease and stroke events.

Results: A total of 307 855 women were included. Overall, the mean (SD) ages at menarche, menopause, and reproductive life span were 13.0 (1.5) years, 50.2 (4.4) years, and 37.2 (4.6) years, respectively. Pooled analyses showed that women with a very short reproductive life span (<30 years) were at 1.71 (95% CI, 1.58-1.84) times higher risk of incident CVD events than women with a reproductive life span of 36 to 38 years after adjustment for covariates. This association remained unchanged when adjusted for age at menarche but was attenuated to 1.26 (95% CI, 1.09-1.46) when adjusted for age at menopause. There was a significant interaction between reproductive life span and age at menarche associated with CVD risk (P < .001). Women who had both short reproductive life span (<33 years) and early menarche (age ≤11 years) had the highest risk of CVD (hazard ratio, 2.06; 95% CI, 1.76-2.41) compared with those with a reproductive life span of 36 to 38 years and menarche at age 13 years.

Conclusions And Relevance: Short reproductive life span was associated with an increased risk of nonfatal CVD events in midlife, and the risk was significantly higher for women with early age at menarche.
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http://dx.doi.org/10.1001/jamacardio.2020.4105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495334PMC
December 2020

Maternal Influenza A(H1N1) Immunization During Pregnancy and Risk for Autism Spectrum Disorder in Offspring : A Cohort Study.

Ann Intern Med 2020 10 1;173(8):597-604. Epub 2020 Sep 1.

Karolinska Institutet, Stockholm, Sweden, and Statens Serum Institut, Copenhagen, Denmark (B.P.).

Background: There are concerns that influenza vaccine exposure during pregnancy may be associated with increased risk for autism spectrum disorder (ASD).

Objective: To examine the risk for ASD in offspring of mothers who were vaccinated against influenza A(H1N1)pdm09 ("swine flu") during pregnancy.

Design: Population-based cohort study using nationwide registers.

Setting: Seven health care regions in Sweden.

Participants: Live births between October 2009 and September 2010, with follow-up through December 2016. In total, 39 726 infants were prenatally exposed to H1N1 vaccine (13 845 during the first trimester) and 29 293 infants were unexposed.

Measurements: Cox regression was used to estimate hazard ratios (HRs) for the primary outcome, ASD, before and after adjustment for potential confounders. The secondary outcome was autistic disorder (AD).

Results: Mean follow-up was 6.7 years in both unexposed and exposed children. During follow-up, 394 (1.0%) vaccine-exposed and 330 (1.1%) unexposed children had a diagnosis of ASD. In adjusted analyses, prenatal exposure to H1N1 vaccination was not associated with a later diagnosis of ASD (adjusted HR [aHR], 0.95 [95% CI, 0.81 to 1.12]) or AD (aHR, 0.96 [CI, 0.80 to 1.16]). The 6-year standardized cumulative incidence difference between the unexposed and exposed children was 0.04% (CI, -0.09% to 0.17%) for ASD and 0.02% (CI, -0.09% to 0.14%) for AD. Restricting the analysis to vaccination in the first trimester of pregnancy did not influence risk estimates (aHR, 0.92 [CI, 0.74 to 1.16] for ASD and 0.91 [CI, 0.70 to 1.18] for AD).

Limitation: Data on H1N1 influenza infection are lacking.

Conclusion: This large cohort study found no association between maternal H1N1 vaccination during pregnancy and risk for ASD in the offspring.

Primary Funding Source: Swedish Research Council.
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http://dx.doi.org/10.7326/M20-0167DOI Listing
October 2020

Risk of dementia and death in very-late-onset schizophrenia-like psychosis: A national cohort study.

Schizophr Res 2020 09 14;223:220-226. Epub 2020 Aug 14.

Department of Community Mental Health, University of Haifa, Haifa, Israel. Electronic address:

Knowledge is limited regarding the risks of death and dementia in very-late onset schizophrenia-like psychosis (VLOS). This study aims to scrutinize the associations between VLOS with the risks of death and dementia. Based on a prospective Israeli cohort study with national coverage, 94,120 persons without dementia or schizophrenia diagnoses aged 60 to 90 in 2012 were followed-up for the risks of dementia or death from 2013 to 2017. VLOS was classified as present from the age of the first ICD-9 diagnosis during follow-up, otherwise as absent. Hazard ratios (HR) with confidence intervals (95% CI) were computed with survival models to quantify the associations between VLOS and the risks of death and dementia, without and with adjustment for confounding. Nine sensitivity analyses were computed to examine the robustness of the results. The group with VLOS, compared to the group without, had higher death (n = 61, 18.5% vs. n = 7028, 7.5%, respectively) and dementia (n = 64, 19.5% vs. n = 5962, 6.4%, respectively) rates. In the primary analysis, the group with VLOS compared to the group without had increased risks of death (unadjusted HR = 3.10, 95% CI = 2.36, 4.06, P < .001; adjusted HR = 2.89, 95% CI = 2.15, 3.89; P < .001) and dementia (unadjusted HR = 3.81, 95% CI = 2.90, 4.99, P < .001; adjusted HR = 2.67, 95% CI = 1.82, 3.91; P < .001). The results remained statistically significant (P < .05) in all sensitivity analyses, including among persons without antipsychotic medication. The results may support notions of increased dementia risk and accelerated aging in VLOS, or that VLOS is a prodromal state of dementia.
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http://dx.doi.org/10.1016/j.schres.2020.07.020DOI Listing
September 2020

Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies.

Hum Reprod 2020 08;35(8):1933-1943

The University of Queensland, Epidemiology and Biostatistics Division, School of Public Health, Brisbane, Queensland, Australia.

Study Question: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause?

Summary Answer: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause.

What Is Known Already: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear.

Study Design, Size, Duration: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis.

Participants/materials, Setting, Methods: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause.

Main Results And The Role Of Chance: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT.

Limitations, Reasons For Caution: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results.

Wider Implications Of The Findings: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD.

Study Funding/competing Interest(s): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.
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http://dx.doi.org/10.1093/humrep/deaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453420PMC
August 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Inherited Risk for Autism Through Maternal and Paternal Lineage.

Biol Psychiatry 2020 09 2;88(6):480-487. Epub 2020 Apr 2.

Jockey Club School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Autism spectrum disorder (ASD) is highly familial, with a positively skewed male-to-female ratio that is purported to arise from the so-called female protective effect. A serious implication of a female protective effect is that familial ASD liability would be expected to aggregate asymptomatically in sisters of affected probands, who would incur elevated rates of ASD among their offspring. Currently, there exist no data on second-generation recurrence rates among families affected by ASD.

Methods: We analyzed data from the Swedish National Patient Register and the Multi-Generation Register for a cohort of children born between 2003 and 2012. ASD was ascertained in both the child and parental generations.

Results: Among 847,732 children, 13,103 (1.55%) children in the cohort were diagnosed with ASD. Among their maternal/paternal aunts and uncles, 1744 (0.24%) and 1374 (0.18%) were diagnosed with ASD, respectively. Offspring of mothers with a sibling(s) diagnosed with ASD had higher rates of ASD than the general population (relative risk, 3.05; 95% confidence interval, 2.52-3.64), but not more than would be predicted for second-degree relatives within a generation, and only slightly more than was observed for fathers with siblings with ASD (relative risk, 2.08; 95% confidence interval, 1.53-2.67). Models adjusting for temporal trends and for psychiatric history in the parental generation did not alter the results.

Conclusions: These findings establish a robust general estimate of ASD transmission risk for siblings of individuals affected by ASD, the first ever reported. Our findings do not suggest female protective factors as the principal mechanism underlying the male sex bias in ASD.
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http://dx.doi.org/10.1016/j.biopsych.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483301PMC
September 2020

Are Visual Memory Deficits in Recent-Onset Psychosis Degenerative? Response to Smucny et al.

Am J Psychiatry 2020 04;177(4):356-357

Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London (Zanelli, Reichenberg); Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston (Mollon); Department of Psychiatry (Sandin, Reichenberg), Department of Environmental Medicine and Public Health, and Friedman Brain Institute (Reichenberg), Icahn School of Medicine at Mount Sinai, New York.

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http://dx.doi.org/10.1176/appi.ajp.2019.19080845rDOI Listing
April 2020

Further Analysis of Cognitive Change in Schizophrenia and Other Psychoses in the Decade Following the First Episode: Response to Panayiotou et al.

Am J Psychiatry 2020 04;177(4):354-355

Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London (Zanelli, Reichenberg); Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston (Mollon); Department of Psychiatry (Sandin, Reichenberg), Department of Environmental Medicine and Public Health, and Friedman Brain Institute (Reichenberg), Icahn School of Medicine at Mount Sinai, New York.

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http://dx.doi.org/10.1176/appi.ajp.2019.19090972rDOI Listing
April 2020

Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder.

Biol Psychiatry 2020 06 22;87(12):1045-1051. Epub 2020 Jan 22.

Division of Tics, OCD, and Related Disorders, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: While genetic variation has a known impact on the risk for obsessive-compulsive disorder (OCD), there is also evidence that there are maternal components to this risk. Here, we partitioned sources of variation, including direct genetic and maternal effects, on risk for OCD.

Methods: The study population consisted of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, and December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013. Diagnostic information about OCD was obtained using the Swedish National Patient Register.

Results: A total of 7184 individuals in the birth cohort (0.87%) were diagnosed with OCD. After exploring various generalized linear mixed models to fit the diagnostic data, genetic maternal effects accounted for 7.6% (95% credible interval: 6.9%-8.3%) of the total variance in risk for OCD for the best model, and direct additive genetics accounted for 35% (95% credible interval: 32.3%-36.9%). These findings were robust under alternative models.

Conclusions: Our results establish genetic maternal effects as influencing risk for OCD in offspring. We also show that additive genetic effects in OCD are overestimated when maternal effects are not modeled.
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http://dx.doi.org/10.1016/j.biopsych.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023336PMC
June 2020

Omega-3 and -6 Fatty Acid Intake and Colorectal Cancer Risk in Swedish Women's Lifestyle and Health Cohort.

Cancer Res Treat 2020 Jul 6;52(3):848-854. Epub 2020 Mar 6.

International Agency for Research on Cancer, Lyon, France.

Purpose: We aimed to assess the association between the dietary intake of fish-derived omega-3 polyunsaturated fatty acids and the risk of colorectal cancer among Swedish women.

Materials And Methods: A total of 48,233 women with information on dietary intake were included in the analysis. Participants were followed for incident colorectal cancer until 31 December 2012. Cox proportional hazard models were used to assess the association between baseline fatty acid intake and colorectal cancer risk. All analyses were stratified by colon and rectal cancers.

Results: During a median of 21.3 years of follow-up, a total of 344 colorectal cancer cases were ascertained. Although there was no overall association between omega-3 fatty acid intake and colorectal cancer risk, high intake of fish-derived docosahexaenoic acid was associated with reduced risk of rectal cancer (hazard ratios for the third and the highest quartiles were 0.59 (95% confidence interval [CI], 0.37 to 0.96) and 0.62 (95% CI, 0.39 to 0.98), respectively).

Conclusion: In conclusion, we found only limited support for an association between omega-3 polyunsaturated fatty acids and colorectal cancer in a large Swedish cohort of middle-aged women.
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http://dx.doi.org/10.4143/crt.2019.550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373878PMC
July 2020

Identification of newborns at risk for autism using electronic medical records and machine learning.

Eur Psychiatry 2020 02 26;63(1):e22. Epub 2020 Feb 26.

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Current approaches for early identification of individuals at high risk for autism spectrum disorder (ASD) in the general population are limited, and most ASD patients are not identified until after the age of 4. This is despite substantial evidence suggesting that early diagnosis and intervention improves developmental course and outcome. The aim of the current study was to test the ability of machine learning (ML) models applied to electronic medical records (EMRs) to predict ASD early in life, in a general population sample.

Methods: We used EMR data from a single Israeli Health Maintenance Organization, including EMR information for parents of 1,397 ASD children (ICD-9/10) and 94,741 non-ASD children born between January 1st, 1997 and December 31st, 2008. Routinely available parental sociodemographic information, parental medical histories, and prescribed medications data were used to generate features to train various ML algorithms, including multivariate logistic regression, artificial neural networks, and random forest. Prediction performance was evaluated with 10-fold cross-validation by computing the area under the receiver operating characteristic curve (AUC; C-statistic), sensitivity, specificity, accuracy, false positive rate, and precision (positive predictive value [PPV]).

Results: All ML models tested had similar performance. The average performance across all models had C-statistic of 0.709, sensitivity of 29.93%, specificity of 98.18%, accuracy of 95.62%, false positive rate of 1.81%, and PPV of 43.35% for predicting ASD in this dataset.

Conclusions: We conclude that ML algorithms combined with EMR capture early life ASD risk as well as reveal previously unknown features to be associated with ASD-risk. Such approaches may be able to enhance the ability for accurate and efficient early detection of ASD in large populations of children.
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http://dx.doi.org/10.1192/j.eurpsy.2020.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315872PMC
February 2020

Cohort profile: Epidemiology and Genetics of Obsessive-compulsive disorder and chronic tic disorders in Sweden (EGOS).

Soc Psychiatry Psychiatr Epidemiol 2020 Oct 6;55(10):1383-1393. Epub 2020 Jan 6.

Division of Tics, OCD and Related Disorders, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: The EGOS study (Epidemiology and Genetics of Obsessive-compulsive disorder and chronic tic disorders in Sweden) is a large-scale, epidemiological, prospective cohort that is used to identify genetic and environmental risk factors in the etiology of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD).

Methods: Individuals born between January 1954 and December 1998 with at least two diagnoses of OCD or CTD at different timepoints in the National Patient Register (NPR), and followed between January 1997 and December 2012, represent the EGOS source population (n = 20,374). The Swedish Multi-Generation Registry (MGR) are then used to define family relatedness for all cases and additional phenotypic and demographic data added to the resultant database. To create an epidemiologically valid subset of the source cohort that also includes biospecimens and additional phenotyping, we contact cases from within the source population. To date, 6832 invitations have been sent out and 1853 (27%) have elected to participate in the EGOS biospecimen collection.

Results: To date, 1608 biological samples have been collected, of which 1249 are genotyped and 832 supplementary Obsessive-Compulsive Inventory-Revised (OCI-R) and/or Florida Obsessive-Compulsive Inventory (FOCI) have been completed by individuals with OCD and/or CTD, age 16-64 years. DNA samples are genotyped using Infinium Global Screening Array and will undergo whole-exome sequencing in the future. Detailed information is available for each individual through linkage to the Swedish national registers, e.g., identification of additional psychiatric diagnoses, medical diagnoses, birth-related variables, and relevant demographic and social data.

Conclusion: EGOS benefits from a genetically homogeneous sample with epidemiological ascertainment, minimizing the risk of confounding due to population stratification on ascertainment bias. In addition, this study is built upon clinical diagnoses of OCD and CTD in specialized psychiatric care, which reduces further biases and case misclassification.
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http://dx.doi.org/10.1007/s00127-019-01822-7DOI Listing
October 2020

Antidepressants and the Risk of Dementia: Appropriate Consideration of Confounding by Indication.

Am J Geriatr Psychiatry 2020 04 9;28(4):499-500. Epub 2019 Dec 9.

Department of Community Mental Health, University of Haifa (AK, AR, SZL), Haifa, Israel. Electronic address:

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http://dx.doi.org/10.1016/j.jagp.2019.12.004DOI Listing
April 2020

Amount and Intensity of Leisure-Time Physical Activity and Lower Cancer Risk.

J Clin Oncol 2020 03 26;38(7):686-697. Epub 2019 Dec 26.

Brigham and Women's Hospital and Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA.

Purpose: To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.

Methods: Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( < .05) and 95% CIs (< 1.0).

Results: A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.

Conclusion: Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
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http://dx.doi.org/10.1200/JCO.19.02407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048166PMC
March 2020

Reproductive stoppage in autism spectrum disorder in a population of 2.5 million individuals.

Mol Autism 2019 11;10:45. Epub 2019 Dec 11.

1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden.

Background: It has been suggested that parents of children with autism spectrum disorder (ASD) curtail their reproduction, a phenomenon known as reproductive stoppage. To investigate the presence of reproductive stoppage, we followed the reproduction in mothers of children with or without an ASD diagnosis using Swedish population-based registries.

Methods: We followed all families with first child born in 1987 or later. In total 2,521,103 children, nested within 1,270,017 mothers, were included. Exposure was presence of ASD diagnosis in earlier born siblings, and outcome was considered as (1) inter-pregnancy interval and (2) number of subsequent children.

Results: Analyses of inter-pregnancy intervals showed that the association differed across birth orders, with a lower rate of second children when first child had ASD diagnosis, but an increased rate of third and higher birth orders in families where a previous child had an ASD diagnosis. When all birth orders were simultaneously considered, families with a child with an ASD diagnosis were less likely to have another child (hazard ratio (HR), 0.79; 95% confidence interval [95% CI], 0.78-0.80). However, when adjusted for birth order, the association was close to null (HR, 0.97; 95% CI, 0.96-0.99), and after additional adjustments (maternal age, birth period, sex, paternal age, and maternal education), the association disappeared (HR, 1.00; 95% CI, 0.99-1.02). In analyses of subsequent children, after adjustment for covariates, families with an ASD diagnosis had 4% more subsequent children (rate ratio, 1.04; 95% CI, 1.03-1.05).

Limitations: The study was undertaken in a country with largely tax-funded healthcare; results may not generalize to other societies. Following the current dominating umbrella concept of ASD, we did not differentiate between the ASD sub-diagnoses; it is possible that reproductive patterns can be dependent on ASD subtypes and the severity and composition of ASD phenotypes and comorbidities.

Conclusions: This study does not support a universal reproductive stoppage effect in ASD families, when birth order and other factors are considered. Therefore, proper attention to birth order and other factors may alleviate potential bias in familial aggregation studies of ASD.
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http://dx.doi.org/10.1186/s13229-019-0300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907273PMC
June 2020

Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort.

JAMA Psychiatry 2019 10;76(10):1035-1043

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Importance: The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries.

Objective: To estimate the additive genetic, maternal, and environmental effects in ASD.

Design, Setting, And Participants: Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018.

Main Outcomes And Measures: Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects.

Results: The analytic sample included 2 001 631 individuals, of whom 1 027 546 (51.3%) were male. Among the entire sample, 22 156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD.

Conclusions And Relevance: Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.1411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646998PMC
October 2019
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