Non-parametric estimation of population size changes from the site frequency spectrum.

Changes in population size is a useful quantity for understanding the evolutionary history of a species. Genetic variation within a species can be summarized by the site frequency spectrum (SFS). For a sample of size n, the SFS is a vector of length n - 1 where entry i is the number of sites where the mutant base appears i times and the ancestral base appears n - i times. We present a new method, CubSFS, for estimating the changes in population size of a panmictic population from an observed SFS. First, we provide a straightforward proof for the expression of the expected site frequency spectrum depending only on the population size. Our derivation is based on an eigenvalue decomposition of the instantaneous coalescent rate matrix. Second, we solve the inverse problem of determining the changes in population size from an observed SFS. Our solution is based on a cubic spline for the population size. The cubic spline is determined by minimizing the weighted average of two terms, namely (i) the goodness of fit to the observed SFS, and (ii) a penalty term based on the smoothness of the changes. The weight is determined by cross-validation. The new method is validated on simulated demographic histories and applied on unfolded and folded SFS from 26 different human populations from the 1000 Genomes Project.

The importance of distinguishing between the odds ratio and the incidence rate ratio in GWAS.

BACKGROUND: In recent years, genome wide association studies have identified many genetic variants that are consistently associated with common complex diseases, but the amount of heritability explained by these risk alleles is still low. Part of the missing heritability may be due to genetic heterogeneity and small sample sizes, but non-optimal study designs in many genome wide association studies may also have contributed to the failure of identifying gene variants causing a predisposition to disease. The normally used odds ratio from a classical case-control study measures the association between genotype and being diseased. In comparison, under incidence density sampling, the incidence rate ratio measures the association between genotype and becoming diseased. We estimate the differences between the odds ratio and the incidence rate ratio under the presence of events precluding the disease of interest. Such events may arise due to pleiotropy and are known as competing events. In addition, we investigate how these differences impact the association test. METHODS: We simulate life spans of individuals whose gene variants are subject to competing events. To estimate the association between genotype and disease, we applied classical case-control studies and incidence density sampling. RESULTS: We find significant numerical differences between the odds ratio and the incidence rate ratio when the fact that gene variant may be associated with competing events, e.g. lifetime, is ignored. The only scenario showing little or no difference is an association with a rare disease and no other present associations. Furthermore, we find that p-values for association tests differed between the two study designs. CONCLUSIONS: If the interest is on the aetiology of the disease, a design based on incidence density sampling provides the preferred interpretation of the estimate. Under a classical case-control design and in the presence of competing events, the change in p-values in the association test may lead to false positive findings and, more importantly, false negative findings. The ranking of the SNPs according to p-values may differ between the two study designs.

Time trend in diagnosing dementia in secondary care.

BACKGROUND: To study the trend of diagnosing dementia in the secondary health care sector over time, we conducted a nationwide longitudinal study of the incidence and prevalence of registered dementia diagnoses in the Danish national hospital registers. METHODS: All Danish residents born before 1964 and alive at their 40th birthday were followed from their 40th birthday or January 1, 1970, whichever came later, to the date of the first dementia diagnosis recorded in the hospital registers, the date of emigration, date of death, or December 31, 2004, whichever came first. The age- and period-specific incidence and prevalence of dementia were calculated and compared to estimates from large community-based cohort studies in Europe. RESULTS: The study population consisted of 4,723,838 persons with 81,090,583 person-years of follow-up. 154,152 dementia cases were registered from 1970 to 2004. The incidence and prevalence of registered dementia diagnoses showed an increasing trend over time. In 2003, the age-standardized incidence rate ratio was 0.66 when compared to estimates from large European community-based cohort studies. CONCLUSIONS: The study shows a marked improvement in the diagnostic rate of dementia in secondary care over time and indicates that this sector can be an important point of entry for patients with dementia.

Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study.

BACKGROUND: This study aimed to determine whether there is an association between hysterectomy and dementia. METHODS: All female Danish residents born before 1966, alive on their 40th birthday and without a dementia diagnosis prior to 1977 (n = 2,313,388) were followed from January 1, 1977, or the age of 40, whichever came later, until dementia diagnosis, death, emigration or December 31, 2006, whichever came first. The relative risks (RR) for developing dementia in women with hysterectomy/oophorectomy compared to referent women were calculated. RESULTS: Overall, hysterectomy did not increase the risk of dementia. When stratified by age at dementia diagnosis, hysterectomy was associated with an increased risk for early-onset dementia before the age of 50: hysterectomy alone (RR = 1.38, 95% confidence interval (CI) = 1.07-1.78), with unilateral oophorectomy (RR = 2.10, 95% CI = 1.28-3.45), with bilateral oophorectomy (RR = 2.33, 95% CI = 1.44-3.77). The younger the age at hysterectomy/oophorectomy, the greater was the risk. CONCLUSIONS: Although statistically significant, the association between premenopausal hysterectomy and early-onset dementia is uncertain due to study limitations. Premenopausal bilateral oophorectomy is associated with a higher risk, suggesting a dose effect of premature estrogen deficiency on dementia. The age-dependent effect suggests that the younger brain is probably more vulnerable to estrogen deficiency.

Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth.

BACKGROUND: Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. METHODS: This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). RESULTS: Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. CONCLUSIONS: Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders.

IMPORTANCE: Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE: To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES: Age and sex. MAIN OUTCOMES AND MEASURES: Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS: During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE: This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research.

Environmental and familial risk factors for psychotic and non-psychotic severe depression.

BACKGROUND: Severe unipolar depression can be classified as either psychotic depression (PD) or non-psychotic depression (non-PD). A number of biological and clinical differences have been detected between PD and non-PD, but it remains unknown whether risk factors for the two subtypes also differ. The aim of the present study was therefore to investigate whether a number of potential risk factors influenced the risk of developing PD and non-PD to different extents. METHODS: This is a register-based historical prospective cohort study following all 2.4 million individuals born in Denmark between 1955 and 1990. During follow-up 2183 and 9101 individuals were registered in the Danish Psychiatric Central Research Register with PD and non-PD respectively. The association between risk factors and the development of PD and non-PD was estimated by survival analysis (Poisson regression) and expressed as incidence rate ratios (IRR). RESULTS: The most consistent finding of the study was that of a general overlap in familial and environmental risk factors for PD and non-PD. However, a parental history of bipolar disorder was a risk factor for PD (mother, IRR=1.66, p=0.003. Father, IRR=1.56, p=0.040) and not for non-PD (mother, IRR=0.92, p=0.430. Father, IRR=1.08, p=0.552). Conversely, a positive family history of schizophrenia was associated with neither PD nor non-PD LIMITATIONS: Diagnoses were assigned as part of routine clinical practice. CONCLUSION: Our findings justify the distinction between PD and non-PD in the current diagnostic manuals. Furthermore, the fact that parental bipolar disorder and not schizophrenia was a risk factor for PD supports the Kraepelinian dichotomy.

A SAS-macro for estimation of the cumulative incidence using Poisson regression.

In survival analyses, we often estimate the hazard rate of a specific cause. Sometimes the main focus is not the hazard rates but the cumulative incidences, i.e., the probability of having failed from a specific cause prior to a given time. The cumulative incidences may be calculated using the hazard rates, and the hazard rates are often estimated by the Cox regression. This procedure may not be suitable for large studies due to limited computer resources. Instead one uses Poisson regression, which approximates the Cox regression. Rosthøj et al. presented a SAS-macro for the estimation of the cumulative incidences based on the Cox regression. I present the functional form of the probabilities and variances when using piecewise constant hazard rates and a SAS-macro for the estimation using Poisson regression. The use of the macro is demonstrated through examples and compared to the macro presented by Rosthøj et al.

Young males have a higher risk of developing schizophrenia: a Danish register study.

BACKGROUND: Gender differences are commonly reported in schizophrenia research, especially with regard to age at onset. Few studies have reported the age- and gender-specific incidence of schizophrenia in people aged up to 71 years, and no studies have reported the cumulative incidence of schizophrenia in people aged up to 71 years. METHOD: Two cohorts were established by linking data from the Danish Civil Registration System (DCRS) with data from the Danish Psychiatric Central Register (DPCR), which covers all incident cases of schizophrenia from 15 to 71 years. We estimated the gender- and age-specific incidence rates of schizophrenia for people aged up to 71 years. We also estimated the cumulative incidences. RESULTS: The incidence rates for males significantly exceeded those for females in the age range from 17 to 40 years. By their 72nd birthday, 1.59% of males and 1.17% of females had developed schizophrenia. CONCLUSION: Male sex is a major risk factor for the development of schizophrenia.