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Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study.

https://arctichealth.org/en/permalink/ahliterature282224
Source
Int J Cancer. 2017 Jun 01;140(11):2461-2472
Publication Type
Article
Date
Jun-01-2017
Author
Stine Kjaer Urhoj
Ole Raaschou-Nielsen
Anne Vinkel Hansen
Laust Hvas Mortensen
Per Kragh Andersen
Anne-Marie Nybo Andersen
Source
Int J Cancer. 2017 Jun 01;140(11):2461-2472
Date
Jun-01-2017
Language
English
Publication Type
Article
Keywords
Adult
Cohort Studies
Denmark
Family
Humans
Middle Aged
Neoplasms - etiology
Paternal Age
Proportional Hazards Models
Registries
Risk factors
Abstract
Cancer initiation is presumed to occur in utero for many childhood cancers and it has been hypothesized that advanced paternal age may have an impact due to the increasing number of mutations in the sperm DNA with increasing paternal age. We examined the association between paternal age and specific types of childhood cancer in offspring in a large nationwide cohort of 1,904,363 children born in Denmark from 1978 through 2010. The children were identified in the Danish Medical Birth Registry and were linked to information from other national registers, including the Danish Cancer Registry. In total, 3,492 children were diagnosed with cancer before the age of 15 years. The adjusted hazard ratio of childhood cancer according to paternal age was estimated using Cox proportional hazards regressions. We found a 13% (95% confidence interval: 4-23%) higher hazard rate for every 5 years advantage in paternal age for acute lymphoblastic leukemia, while no clear association was found for acute myeloid leukemia (hazard ratio pr. 5 years?=?1.02, 95% confidence interval: 0.80-1.30). The estimates for neoplasms in the central nervous system suggested a lower hazard rate with higher paternal age (hazard ratio pr. 5 years?=?0.92, 95% confidence interval: 0.84-1.01). No clear associations were found for the remaining childhood cancer types. The findings suggest that paternal age is moderately associated with a higher rate of childhood acute lymphoblastic leukemia, but not acute myeloid leukemia, in offspring, while no firm conclusions could be made for other specific cancer types.
PubMed ID
28257590 View in PubMed
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Advanced paternal age and mortality of offspring under 5 years of age: a register-based cohort study.

https://arctichealth.org/en/permalink/ahliterature256919
Source
Hum Reprod. 2014 Feb;29(2):343-50
Publication Type
Article
Date
Feb-2014
Author
S K Urhoj
L N Jespersen
M. Nissen
L H Mortensen
A-M Nybo Andersen
Author Affiliation
Section of Social Medicine, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, Copenhagen K DK-1014, Denmark.
Source
Hum Reprod. 2014 Feb;29(2):343-50
Date
Feb-2014
Language
English
Publication Type
Article
Keywords
Adult
Child Mortality
Child, Preschool
Congenital Abnormalities - mortality
Denmark
Fathers
Humans
Infant
Infant mortality
Infant, Newborn
Male
Middle Aged
Neoplasms - mortality
Paternal Age
Proportional Hazards Models
Prospective Studies
Registries
Risk
Abstract
Do children born to fathers of advanced age have an increased risk of dying before the age of 5 years?
Children born to fathers aged 40 years or more have an increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes.
Advanced paternal age has previously been associated with adverse reproductive outcomes and some long-term health problems in the offspring. This is possibly due to specific point mutations, a condition known to increase in the sperm with increasing paternal age.
A Danish population-based register study, designed as a prospective cohort study, of 1 575 521 live born children born from 1978 to 2004. The age of the child (in days) was used as the underlying time and the children entered the cohort the day they were born and were followed until 31 December 2009. The children were censored on date of turning 5 years, date of death or date of emigration, whichever occurred first.
Data from population-covering registers from Statistics Denmark including the Integrated Database for Labour Market Research, the Medical Birth Registry and the Registry of Causes of Death was linked using the unique civil registry number. Hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the risk of under-five mortality. The effect of paternal age was examined using restricted cubic splines and paternal age groups.
Compared with children born to fathers aged 30-34 years, a statistically significant excess risk was found for children born to fathers aged 40-44 years [HR: 1.10 (95% CI: 1.00-1.21)] and children born to fathers aged 45+ years [HR: 1.16 (95% CI: 1.02-1.32)]. When only looking at 1-5 year olds, the relative risk (HR) among children born to fathers aged 40-44 years increased to 1.24 (95% CI: 1.00-1.53) and the risk in the oldest paternal age group (45+ years) rose to 1.65 (95% CI: 1.24-2.18). The results suggest that the elevated risk for children of fathers aged 40 years or more was primarily attributed to an elevated risk of dying from congenital malformations, malignancies and external causes.
Specific causes of death might be misclassified; however, this is not likely to be dependent on paternal age. In some cases, the biological father may differ from the father registered. This misclassification is most likely non-differential.
The excess risk of mortality among children born to older fathers is in accordance with the literature. The association needs further attention as it can provide valuable knowledge of the etiology of genetic diseases. Also, the association could become of greater importance in the future if the proportion of fathers aged 40+ years keeps growing.
None.
Notes
Comment In: Hum Reprod. 2014 Feb;29(2):18924316516
Comment In: Eur Urol. 2014 Jun;65(6):1222-324774830
PubMed ID
24316515 View in PubMed
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Advanced paternal age and parental history of schizophrenia.

https://arctichealth.org/en/permalink/ahliterature131103
Source
Schizophr Res. 2011 Dec;133(1-3):125-32
Publication Type
Article
Date
Dec-2011
Author
Brian Miller
Jaana Suvisaari
Jouko Miettunen
Marjo-Riitta Järvelin
Jari Haukka
Antti Tanskanen
Jouko Lönnqvist
Matti Isohanni
Brian Kirkpatrick
Author Affiliation
Department of Psychiatry and Health Behavior, Medical College of Georgia Health Sciences University, Augusta, Georgia 30912, United States. brmiller@georgiahealth.edu
Source
Schizophr Res. 2011 Dec;133(1-3):125-32
Date
Dec-2011
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Aged
Cohort Studies
Family Health
Female
Finland
Humans
Logistic Models
Male
Maternal Age
Middle Aged
Odds Ratio
Paternal Age
Retrospective Studies
Risk factors
Schizophrenia - epidemiology - genetics
Young Adult
Abstract
Advanced paternal age (APA) is a risk factor for nonaffective psychosis (NAP) in the offspring, although the mechanism(s) of this association are not clear. The aim of this study was to examine whether later childbearing can be explained by parental schizophrenia, and in doing so, further evaluate the "de novo mutation" hypothesis for the association between APA and NAP.
Using binary logistic regression, the association between APA and parental history of schizophrenia in the offspring, considering maternal and paternal history separately, was examined in 1) all persons with NAP born in Finland between 1950 and 1969 (Finnish NAP Cohort, n = 13,712), and 2) members of the Northern Finland 1966 Birth Cohort (NFBC 1966, n = 10,224), a general population birth cohort.
In the Finnish NAP Cohort, having a mother with schizophrenia was associated with APA (Odds Ratio [OR] for linear trend = 1.20, 95% confidence interval 1.12-1.29, p
PubMed ID
21937198 View in PubMed
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Advanced paternal age and risk of fetal death: a cohort study.

https://arctichealth.org/en/permalink/ahliterature63286
Source
Am J Epidemiol. 2004 Dec 15;160(12):1214-22
Publication Type
Article
Date
Dec-15-2004
Author
Anne-Marie Nybo Andersen
Kasper Daniel Hansen
Per Kragh Andersen
George Davey Smith
Author Affiliation
Department of Social Medicine, University of Copenhagen, Copenhagen, Denmark. ana@niph.dk
Source
Am J Epidemiol. 2004 Dec 15;160(12):1214-22
Date
Dec-15-2004
Language
English
Publication Type
Article
Keywords
Abortion, Spontaneous - etiology
Adult
Cohort Studies
Denmark
Female
Fetal Death - etiology
Humans
Life Style
Male
Maternal Age
Middle Aged
Paternal Age
Pregnancy
Reproductive history
Research Support, Non-U.S. Gov't
Risk factors
Survival Analysis
Abstract
A possible detrimental paternal age effect on offspring health due to mutations of paternal origin should be reflected in an association between paternal age and fetal loss. The authors used data from a prospective study of 23,821 pregnant women recruited consecutively to the Danish National Birth Cohort from 1997 to 1999 to assess the association between paternal age and fetal death. Fathers of the pregnancies were identified by record linkage to population registers. The paternal age-related risks of fetal death and its components, early and late fetal loss, were estimated using survival analysis. Pregnancies fathered by a man aged 50 or more years (n = 124) had almost twice the risk of ending in a fetal loss compared with pregnancies with younger fathers (hazard ratio = 1.88, 95% confidence interval: 0.93, 3.82), after adjustment for maternal age, reproductive history, and maternal lifestyle during pregnancy. Various approaches to adjustment for potential residual confounding of the relation by maternal age did not affect the relative risk estimates. The paternal age-related risk of late fetal death was higher than the risk of early fetal death and started to increase from the age of 45 years. It should, however, be interpreted cautiously because of the restricted number of fetal deaths.
PubMed ID
15583374 View in PubMed
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Advanced Paternal Age and Risk of Musculoskeletal Congenital Anomalies in Offspring.

https://arctichealth.org/en/permalink/ahliterature277020
Source
Birth Defects Res B Dev Reprod Toxicol. 2015 Dec;104(6):273-80
Publication Type
Article
Date
Dec-2015
Author
Stine Kjaer Urhoj
Laust Hvas Mortensen
Anne-Marie Nybo Andersen
Source
Birth Defects Res B Dev Reprod Toxicol. 2015 Dec;104(6):273-80
Date
Dec-2015
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Child
Child, Preschool
Congenital Abnormalities - epidemiology
Denmark - epidemiology
Humans
Infant
Infant, Newborn
Middle Aged
Musculoskeletal Abnormalities - epidemiology
Odds Ratio
Paternal Age
Risk factors
Abstract
Previous research suggests that advanced paternal age increases the risk of musculoskeletal congenital anomalies (CAs) in offspring, but findings are inconsistent. This study aims to investigate the risk of musculoskeletal CAs according to paternal age at birth in an unselected population covering cohort of children.
A register-based prospective study of 1,605,885 children born in Denmark, 1978-2004, using information from record-linked health and administrative registers. The association between paternal age and overall musculoskeletal CAs, limb anomalies, craniosynostosis, skeletal dysplasias, syndromic musculoskeletal CAs, and other musculoskeletal CAs were investigated by multiple logistic regression analysis.
For overall musculoskeletal CAs, a slightly higher risk per 10-year increase in paternal age was found (odds ratio [OR] = 1.06 [95% CI: 1.01-1.11; where CI is confidence interval]). A 26% (95% CI: 2-56%) excess risk was found for fathers aged 50+ years compared to fathers aged 30-34 years. For syndromic musculoskeletal CAs, excess risks were found for fathers aged 40+ years, compared to fathers aged 30-34 years (40-44: OR = 1.38 [95% CI: 1.01-1.88], 45-49: OR = 1.45 [95% CI: 0.89-2.34], 50+: OR = 1.42 [95% CI: 0.73-2.79]). The risks in all other subgroups of musculoskeletal CAs were increased for fathers aged 50+ years.
A slightly higher risk for overall musculoskeletal CAs in offspring was found with increasing paternal age, mainly due to an excess risk of syndromic musculoskeletal CAs for fathers aged 40+ years. While associations between paternal age 50+ years and increased risk of all subtypes of musculoskeletal CAs were indicated, advanced paternal age likely plays a minor role in the etiology of these anomalies.
PubMed ID
26663788 View in PubMed
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Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark.

https://arctichealth.org/en/permalink/ahliterature289812
Source
Eur J Epidemiol. 2017 03; 32(3):227-234
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
03-2017
Author
Stine Kjaer Urhoj
Per Kragh Andersen
Laust Hvas Mortensen
George Davey Smith
Anne-Marie Nybo Andersen
Author Affiliation
Section of Social Medicine, Department of Public Health, University of Copenhagen, Oster Farimagsgade 5, POB 2099, 1014, Copenhagen K, Denmark. stur@sund.ku.dk.
Source
Eur J Epidemiol. 2017 03; 32(3):227-234
Date
03-2017
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adult
Cohort Studies
Denmark - epidemiology
Female
Humans
Male
Middle Aged
Paternal Age
Pregnancy
Proportional Hazards Models
Registries - statistics & numerical data
Risk factors
Stillbirth - epidemiology
Young Adult
Abstract
Advanced paternal age has been associated with a variety of rare conditions and diseases of great public health impact. An increased number of de novo point mutations in sperm with increasing age have been suggested as a mechanism, which would likely also affect fetal viability. We examined the association between paternal age and stillbirth rate in a large nationwide cohort. We identified all pregnancies in Denmark from 1994 to 2010 carried to a gestational age of at least 22 completed weeks (n = 944,031) as registered in national registers and linked to individual register data about the parents. The hazard ratio of stillbirth according to paternal age was estimated, adjusted for maternal age in 1-year categories, year of outcome, and additionally parental educational levels. The relative rate of stillbirth (n = 4946) according to paternal age was found to be J-shaped with the highest hazard ratio for fathers aged more than 40 years when paternal age was modelled using restricted cubic splines. When modelled categorically, the adjusted hazard ratios of stillbirth were as follows:
Notes
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PubMed ID
28271174 View in PubMed
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Advanced paternal age, mortality, and suicide in the general population.

https://arctichealth.org/en/permalink/ahliterature143004
Source
J Nerv Ment Dis. 2010 Jun;198(6):404-11
Publication Type
Article
Date
Jun-2010
Author
Brian Miller
Antti Alaräisänen
Jouko Miettunen
Marjo-Riitta Järvelin
Hannu Koponen
Pirkko Räsänen
Matti Isohanni
Brian Kirkpatrick
Author Affiliation
Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia 30912, USA. brmiller@mcg.edu
Source
J Nerv Ment Dis. 2010 Jun;198(6):404-11
Date
Jun-2010
Language
English
Publication Type
Article
Keywords
Adult
Age Distribution
Cause of Death
Cohort Studies
Female
Finland - epidemiology
Humans
Longitudinal Studies
Male
Maternal Age
Middle Aged
Parents
Paternal Age
Proportional Hazards Models
Risk factors
Sex Factors
Social Class
Suicide - statistics & numerical data
Abstract
Advanced paternal age is a risk factor for adverse health outcomes in the offspring. In a population-based birth cohort from Finland, 10,965 singleton offspring born in 1966 and alive at age 1 were followed to age 39. Hazard ratios were calculated, adjusting for maternal age, gender, paternal social class, and maternal parity. In females but not in males, increasing paternal age was associated with a linear increased risk of suicide (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.04-1.24, p /=30, the population attributable risk percentage was 13.7% for all deaths and 7.5% for suicides. Parental age at birth may affect suicide and all-causes mortality risk in the offspring in the general population. The causal pathways and specific disorders associated with this increased mortality are largely unknown.
PubMed ID
20531118 View in PubMed
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Advanced reproductive age and fertility.

https://arctichealth.org/en/permalink/ahliterature129652
Source
J Obstet Gynaecol Can. 2011 Nov;33(11):1165-75
Publication Type
Article
Date
Nov-2011
Author
Kimberly Liu
Allison Case
Source
J Obstet Gynaecol Can. 2011 Nov;33(11):1165-75
Date
Nov-2011
Language
English
Publication Type
Article
Keywords
Abortion, Spontaneous
Adult
Aging - physiology
Canada
Chromosome Aberrations - statistics & numerical data
Counseling
Female
Fertility - physiology
Humans
Infertility, Female
MEDLINE
Male
Maternal Age
Middle Aged
Oocyte Donation
Ovary - physiology
Paternal Age
Pregnancy
Reproductive Techniques, Assisted - economics
Risk factors
Treatment Outcome
Abstract
To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging.
This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility.
The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility.
Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010.
The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table).
Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology.
1. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. (II-2A) 2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive. (III-B) 3. Ovarian reserve testing may be considered for women = 35 years of age or for women 40 years of age. Women > 40 years should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian hyperstimulation. (II-2B) 6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a woman's own eggs. (II-2B) 7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established. (II-2A) 8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40. (III-B) 9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small. (II-2C).
PubMed ID
22082792 View in PubMed
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Advancing paternal age and bipolar disorder.

https://arctichealth.org/en/permalink/ahliterature92226
Source
Arch Gen Psychiatry. 2008 Sep;65(9):1034-40
Publication Type
Article
Date
Sep-2008
Author
Frans Emma M
Sandin Sven
Reichenberg Abraham
Lichtenstein Paul
Långström Niklas
Hultman Christina M
Author Affiliation
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden. Emma.Frans@ki.se
Source
Arch Gen Psychiatry. 2008 Sep;65(9):1034-40
Date
Sep-2008
Language
English
Publication Type
Article
Keywords
Adult
Aging - physiology
Bipolar Disorder - diagnosis - epidemiology
Fathers
Female
Humans
Male
Maternal Age
Middle Aged
Paternal Age
Point Mutation - genetics
Prevalence
Registries
Socioeconomic Factors
Sweden - epidemiology
Abstract
CONTEXT: Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders. OBJECTIVES: To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately. DESIGN: A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders. SETTING: Identification of 7,328,100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register. PARTICIPANTS: A total of 13,428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case. Main Outcome Measure Bipolar disorder based on ICD codes at discharge from hospital treatment. RESULTS: An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (
Notes
Comment In: Evid Based Ment Health. 2009 May;12(2):5919395618
PubMed ID
18762589 View in PubMed
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Advancing paternal age and offspring violent offending: a sibling-comparison study.

https://arctichealth.org/en/permalink/ahliterature122731
Source
Dev Psychopathol. 2012 Aug;24(3):739-53
Publication Type
Article
Date
Aug-2012
Author
Ralf Kuja-Halkola
Yudi Pawitan
Brian M D'Onofrio
Niklas Långström
Paul Lichtenstein
Author Affiliation
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, P.O. Box 281, Stockholm 171 77, Sweden. ralf.kuja-halkola@ki.se
Source
Dev Psychopathol. 2012 Aug;24(3):739-53
Date
Aug-2012
Language
English
Publication Type
Article
Keywords
Age Factors
Bipolar Disorder - epidemiology - genetics
Crime - psychology
Criminals - psychology
Fathers
Humans
Male
Paternal Age
Registries
Risk
Risk factors
Schizophrenia - epidemiology - genetics
Siblings - psychology
Sweden
Violence - psychology
Abstract
Children born to older fathers are at higher risk to develop severe psychopathology (e.g., schizophrenia and bipolar disorder), possibly because of increased de novo mutations during spermatogenesis with older paternal age. Because severe psychopathology is correlated with antisocial behavior, we examined possible associations between advancing paternal age and offspring violent offending. Interlinked Swedish national registers provided information on fathers' age at childbirth and violent criminal convictions in all offspring born from 1958 to 1979 (N = 2,359,921). We used ever committing a violent crime and number of violent crimes as indices of violent offending. The data included information on multiple levels; we compared differentially exposed siblings in within-family analyses to rigorously test causal influences. In the entire population, advancing paternal age predicted offspring violent crime according to both indices. Congruent with a causal effect, this association remained for rates of violent crime in within-family analyses. However, in within-family analyses, we found no association with ever committing a violent crime, suggesting that factors shared by siblings (genes and environment) confounded this association. Life-course persistent criminality has been proposed to have a partly biological etiology; our results agree with a stronger biological effect (i.e., de novo mutations) on persistent violent offending.
Notes
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