A simple method for censored age-of-onset data subject to recall bias: Mothers' reports of age of puberty in male twins

Genetic analysis of variation in age of onset of development milestones or psychopathological behaviors has been little researched, owing largely to the computational difficulty of dealing with censored observations. Censored observations arise when the only information on individuals is that they have reached a particular age but without onset having occurred. This paper shows how models can be simply fitted to such data using programs that can perform genetic analysis of categorical data by maximum likelihood. The method is illustrated using the program Mx with data on maternal report of the onset of puberty in twin sons from the Virginia Twin Study of Adolescent Behavioral Development. Frequently, data on age of onset is collected by retrospective recall. This can pose a variety of measurement problems. Suggestions are made for models that account for some of these problems or are robust to their presence. Substantial evidence for telescoping of onset dates is found for the puberty data. If left unaccounted for, these effects can artifactually inflate estimates of common environment effects.     

Mental illness and cognition in relation to age at puberty: a hypothesis

Onset of puberty is usually considered to coincide with the last major step in brain development: the elimination of some 40% of neuronal synapses. Mean pubertal age has declined by some 4 years during the last 100 years. There is a relation between age at puberty and body build, and between body build and mental illness. The difference in body build between schizophrenia (S) and manic-depressive psychosis (MDP) is similar to that between late and early maturers. It is suggested that S affects late-maturing individuals and MDP very early maturers. The observed marked rise in MDP and decline in the most malignant forms of S (non-paranoid) are in agreement with MDP and S as neurodevelopmental disorders occurring at the extremes of maturation. Maturational irregularities are most likely to occur at the extremes, and it is suggested that abbreviation of the regressive process may have led to persistent redundancy of neuronal synapses in MDP and that prolongation of the process past the optimal has yielded an inadequate synaptic density in S. The lack of cerebral abnormality in the majority of MDP and the presence of only subtle structural deficits in S, are in agreement with this. The two disorders are probably as old as mankind, and early puberty is the necessary factor for the development of MDP and late puberty is the necessary factor for that of S. There is an inverse relation between spatial ability and rate of maturation, whereas verbal ability is unaffected by maturational rate. From a previous predominance in both sexes, spatial ability (Performance IQ scores) has been reduced to below verbal ability (Verbal IQ scores) in the female sex and in early maturing males.     

Age of puberty in Iranian girls living in Tehran

The aim of this study was to determine the age of appearance of secondary sexual characteristics in Iranian girls living in Tehran. A cross-sectional study was conducted between 2003 and 2004 on 1420 6–17-year-old females in different parts of Tehran. Data were collected on the basis of a multistage probability sampling. Secondary sexual characteristics were evaluated by inspection and palpation, and were recorded according to Tanner staging. The subjects were asked about the occurrence of menarche and the age of its onset. Generalized additive logistic modelling was used for the analysis of data. The median age (percentile 10–percentile 90) of Tanner 2 of breast development (B2) and Tanner 2 of pubic hair growth (P2) among 1136 girls was 9.74 years (8.23–11.94) and 10.49 years (8.86–12.17), respectively. The ages of the 2.5 percentile for B2 and P2 were 7.42 and 7.03 years, respectively, so the onset of puberty at <7 years and 5 months is considered precocious in this population. The median age of menarche in 399 girls was 12.68 years (11.27–15.96).     

Age of onset of marijuana use impacts inhibitory processing

Difficulties in the ability to successfully inhibit impulsive behaviors have been reported in marijuana (MJ) smokers, yet few studies have made direct comparisons between early (prior to age 16) and late (age 16 or later) onset MJ smokers, specifically during behavioral inhibition tasks. The current study utilized the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) in chronic, heavy MJ smokers and healthy non-MJ smoking controls which revealed a more focal pattern of anterior cingulate activity in controls relative to smokers. Early onset smokers had more focal activation but tended to make more errors of commission relative to late onset smokers, suggesting a possible neural adaptation despite difficulty with behavioral inhibition. Further investigation is warranted, as early exposure to MJ may result in reorganization of critical brain regions.     

Age as a moderator of the secular trend for grip strength in Canada and the United States

Purpose: To determine whether grip strength changed on average over recent decades at each of two age levels (children and adolescents versus adults) in Canada and the US.

Methods: For each sex, weighted least squares regression analyses were performed on mean grip strength values as reported in studies conducted from the 1960s onwards.

Results: Grip strength did not change significantly as a function of year tested in children and adolescents, whereas it declined as a negatively accelerated function of year tested in adults.

Conclusion: The results are contrary to what might be expected given that body weight has increased in both countries in recent decades and given that grip strength has been found to be positively correlated with body weight. It is suggested that there was a concurrent change in a factor that operated to counteract the effect of increased body weight on grip strength, a prime candidate being a decrease in levels of serum vitamin D. It is also suggested that the secular decline in adult grip strength can be explained by a factor that affects muscular function but which has a long latency period, a prime candidate here being obesity history.     

Age of onset in siblings of persons with juvenile Huntinqton disease

The age of onset distribution of Huntington disease (HD) has been defined for siblings of patients who exhibit the disease before age 20. The mean age of onset for the siblings of juvenile onset cases is 26.8 years, which is significantly less than the mean age of onset (39.8) observed in siblings of non-juvenile cases. We have shown that the curve for age of onset in the general affected population is significantly different from that of the juvenile sibships. Furthermore, the significant regression equation suggests that the 'expected age of onset' of a sibling can be predicted from a knowledge of the age of onset of the juvenile proband. This information can be used to predict a range of age of onset for those sibs of juvenile patients who are likely to be asymptomatic heterozygotes with DNA polymorphism studies.     

Precocious puberty in children: A review of imaging findings

Objectives:

This review was aimed at determining the imaging findings in patients with precocious puberty.

Results:

Within a period of 8 years (from 2002 to 2010) there were 53 patients diagnosed with precocious puberty. Out of the 53 patients, 37 had undergone diagnostic imaging to detect the possible organic causes of precocious puberty. Imaging findings were positive in 31 patients and out of that, 3 patients had 2 findings each (34 abnormalities). Of the patients with positive imaging findings, central precocious puberty (gonadotrophin-dependent) was more common (81%; 25/31) and the causes included: tuber cinereum hamartoma (n = 10), glioma (n = 6), pineal gland tumour (n = 4), hydrocephalous (n = 3), arachnoid cyst (n = 2) and others (n = 3). Peripheral precocious puberty (gonadotrophin-independent) causes included: testicular adrenal rest tumour (n = 3), adrenal carcinoma (n = 1), ovarian granulosa thecal cell tumour (n = 1), and tuberous sclerosis (n = 1).

Conclusion:

Positive imaging findings were observed in 84% (31/37) of the subjects. Hypothalamic hamartoma was the most common imaging finding in central precocious puberty while testicular adrenal rest tumour was the most common imaging finding in peripheral precocious puberty.     

Trends in pubertal development in Europe

The secular changes in growth and maturation can be seen as indicators of socio-economic and health status. In most European countries the age of onset of puberty and of menarcheal age has been decreasing during the past few decades. The duration of puberty seems also to decrease, though few studies provide sufficient data to support this postulation. The four Dutch nationwide growth surveys are useful examples assessing the secular trend in pubertal development over the past 45 years. Genetic and environmental factors contribute to the secular changes. Environmental factors seem to be the most important. Recently, attention has been given to substances with oestrogen-like actions that are present in nutrients. The possible role of these substances in growth and maturation is discussed.     

A mixed effects model to estimate timing and intensity of pubertal growth from height and secondary sexual characteristics

Aim: To estimate and compare pubertal growth timing and intensity in height, Tanner stage markers and testis volume.

Subjects and methods: Data on height, genital stage, breast stage and pubic hair stage, testis volume and menarche in 103 boys and 74 girls from the Edinburgh Longitudinal Growth Study were analysed. The SITAR model for height and a novel mixed effects logistic model for Tanner stage and testis volume provided estimates of peak velocity (PV, intensity) and age at peak velocity (APV, timing), both overall (from fixed effects) and for individuals (random effects).

Results: Based on the six markers, mean APV was 13.0–14.0 years in boys and 12.0–13.1 years in girls, with between-subject standard deviations of ～1 year. PV for height was 8–9?cm/year by sex and for testis volume 6?ml/year, while Tanner stage increased by 1.2–1.8 stages per year at its peak. The correlations across markers for APV were 0.6–0.8 for boys and 0.8–0.92 for girls, very significantly higher for girls (p?=?0.005). Correlations for PV were lower, ?0.2–0.6.

Conclusions: The mixed effects models perform well in estimating timing and intensity in individuals across several puberty markers. Age at peak velocity correlates highly across markers, but peak velocity less so.     

Estimation of Variance Components for Age at Menarche in Twin Families

Age at menarche (AAM), time of first menstrual period, is an important developmental milestone in females. Follow-up data from 1,302 adolescent twins and their sisters were used to partition the normal variation in AAM. The proportion of censoring was 14.1%. Both a standard and a survival analysis method were used. The best fitting model from the survival analysis method was an ACE model, where 57% and 23% of the variance in AAM was explained by additive genetic and environmental effects, respectively. The best fitting model when using a standard variance decomposition method was an AE model, where 82% of the variance was explained by additive genetic effects. The lack of correspondence between the results of the two methods was an artefact of the different ascertainment of AAM reports from siblings and twins. After the removal of the sibling sample, both methods indicated that an ACE model was the most likely. Standard and survival analysis methods estimated the proportion of variance explained by additive effects to be 0.50 and 0.54, and common environmental effects to be 0.31 and 0.29, respectively. We conclude that variation in AAM can be explained by additive genetic and common environmental components. Edited by Dorret Boomsma     

Family practice in the United States of America: the first 10 years

Family medicine was officially recognized as an independent discipline and as the twentieth specialty in the USA in 1969, when the American Board of Family Practice was established.

The main achievements of the first 10 years has been the establishment of departments of family practice in two thirds of the medical schools and the growth of graduate training has advanced rapidly from a total of 290 residents in 1970 to over 6,000 in 1978. Developments in group practice, team work, and medical records have been considerable and research is expanding.

In 1976, the 50-year trend of falling numbers of family physicians in the USA was reversed for the first time and excellent progress is also being made in countering the geographical maldistribution of physicians.

The challenges for the future of family practice are different from those in the past and are discussed.

     

Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10⁻⁷), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10⁻⁷), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10⁻⁷). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R²_partial = 0.0061; p = 6.59 × 10⁻⁸) and rs803675 (R²_partial = 0.0060; p = 6.96 × 10⁻⁸). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.     

Age at natural menopause in Spain and the United States: results from the DAMES project.

Our research was undertaken to determine the median age of natural menopause and correlates of the timing of menopause in Spain and the United States (U.S.). A population-based sample of 300 women from Madrid, Spain and a random sample of 293 women from Fallon Community Health plan (FCHP), a health maintenance organization (HMO) in central Massachusetts, were interviewed using a semi-structured questionnaire. Logit analysis and logistic regression were used to estimate the median age at menopause and identify factors associated with it. The median age of natural menopause in Spain is estimated at 51.7 years, and in the U.S., it is 52.6 years. In Spain, women with any children (OR = 0.58, 95% CI: 0.25, 1.36) and a lower body mass index (BMI) (OR = 0.45, 95% CI: 0.27, 0.78) had later ages at menopause while current smokers (OR = 5.51, 95% CI: 1.82, 16.7) had earlier ages of menopause in a multivariate model. A multiplicative interaction between smoking status and parity was identified, and an interaction term included in the multivariate model (OR = 0.58, 95% CI: 0.35, 0.94). In the U.S., household income, marital status, and education level were statistically associated with age at natural menopause in bivariate models. These factors were no longer statistically significant after adjustments in a multivariate model. Oral contraceptive use, cycle length, and cycle regularity were not statistically associated with the age of menopause in either country. The ages of natural menopause in Spain and the U.S. are comparable to other industrialized nations. The factors associated with the timing of natural menopause, in particular smoking and BMI, are consistent with those identified in previous studies.     

Food-borne trematode infections of humans in the United States of America

This review examines the literature on imported (allochthonous) and local (autochthonous) cases of food-borne trematode (FBT) infections in the United States of America (USA) from 1890 to 2009. Most of the literature is concerned with imported cases of the opisthorchiids Clonorchis sinensis and Opisthorchis viverrini. These flukes cause serious pathology in the liver and biliary system of humans. Chronic cases may induce liver (hepatocarcinoma) and bile duct (cholangiocarcinoma) cancers in humans. Clonorchiasis and opithorchiasis are preventable diseases that can be avoided by eating properly cooked freshwater fish products. Several species of lung flukes in the genus Paragonimus are local or imported FBT in the USA. The endemic cycle occurs in the USA with various local snails and crustaceans serving as intermediate hosts. Paragonimids are acquired when humans eat raw or improperly cooked freshwater crustaceans containing metacercarial cysts. Infection can cause severe lung disease and the symptoms of paragonimiasis often mimic those of tuberculosis and other non-helminthic diseases. Paragonimiasis can be avoided by not eating raw or improperly cooked shellfish. The liver fluke Fasciola hepatica can be acquired by eating raw or uncooked vegetation. The cycle exists in the USA involving local snails and aquatic vegetation. Although some cases are local, most are imported by travelers or immigrants. Fascioliasis can cause serious liver and biliary diseases in humans and consumption of tainted vegetation should be avoided. Lesser known FBT have been reported in the USA including species of Alaria, echinostomids, heterophyids, troglotrematids, and a self-induced infection of Plagiorchis. Treatment of the FBT mentioned in this review consists of various regimens of praziquantel, except for F. hepatica where the drug of choice is triclabendazole.     

Individual Differences in Puberty Onset in Girls: Bayesian Estimation of Heritabilities and Genetic Correlations

We report heritabilities for individual differences in female pubertal development at the age of 12. Tanner data on breast and pubic hair development in girls and data on menarche were obtained from a total of 184 pairs of monozygotic and dizygotic twins. Genetic correlations were estimated to determine to what extent the same genes are involved in different aspects of physical development in puberty. A Bayesian estimation approach was taken, using Markov-chain Monte Carlo simulation to estimate model parameters. All three phenotypes were to a significant extent heritable and showed high genetic correlations, suggesting that a common set of genes is involved in the timing of puberty in general. However, gonadarche (menarche and breast development) and adrenarche (pubic hair) are affected by different environmental factors, which does not support the three phenotypes to be regarded as indicators of a unitary physiological factor.