Confounding in association studies: month of birth and multiple sclerosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Fiddes B
PROVIDER: S-EPMC4192561 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth.Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics.We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone.In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives.
| S-EPMC3748787 | biostudies-literature
Project description:A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.
| S-EPMC4212485 | biostudies-literature
Project description:Large-scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding.
| S-EPMC5983059 | biostudies-literature
Project description:IntroductionMany studies have shown that people born in the spring are at a higher risk of developing multiple sclerosis (MS). This may be associated with lower levels of sun exposure, and consequently, lower levels of vitamin D3 during pregnancy. However, these relationships have not been verified thus far in any countries in Central Europe.ObjectiveThe aim of our study was to determine the frequency distribution of births for each calendar month in patients suffering from MS in Poland.MethodsWe analyzed data for 2574 patients diagnosed with MS (1758 women, 816 men) living in Poland for an extended period. We added corrections resulting from the frequency distribution of births for the years in which the patients were born. We applied the Hewitt test for seasonality with Rogerson modification for 3-, 4-, or 6-month pulses or periods. Moreover, we examined the average number hours of sunshine in every month of the year.ResultsThe rank-sums for successive 3- and 4-month segments indicated the period from September to December and from October to December as having a significantly lower incidence (p = 0.027 and p = 0.054, respectively). We did not find a correlation between with hours of sunshine in the first trimester of pregnancy, the child's birth month, and the child developing MS.ConclusionsWe were able to confirm a seasonal variation in the risk of MS in Poland. However, these findings did not correlate with hours of sunshine during the first trimester of pregnancy.
| S-EPMC5383232 | biostudies-literature
Project description:Association studies among admixed populations pose many challenges including confounding of genetic effects due to population substructure and heterogeneity due to different patterns of linkage disequilibrium (LD). We use simulations to investigate controlling for confounding by indicators of global ancestry and the impact of including a covariate for local ancestry. In addition, we investigate the use of an interaction term between a single-nucleotide polymorphism (SNP) and local ancestry to capture heterogeneity in SNP effects. Although adjustment for global ancestry can control for confounding, additional adjustment for local ancestry may increase power when the induced admixture LD is in the opposite direction as the LD in the ancestral population. However, if the induced LD is in the same direction, there is the potential for reduced power because of overadjustment. Furthermore, the inclusion of a SNP by local ancestry interaction term can increase power when there is substantial differential LD between ancestry populations. We examine these approaches in genome-wide data using the University of Southern California's Children's Health Study investigating asthma risk. The analysis highlights rs10519951 (P = 8.5 × 10(-7)), a SNP lacking any evidence of association from a conventional analysis (P = 0.5).
| S-EPMC3626055 | biostudies-literature
Project description:Previous studies have shown that the risk of multiple sclerosis (MS) is associated with season of birth with a higher proportion of MS patients being born in spring. However, this relationship has recently been questioned and may be due to confounding factors. Our aim was to assess the influence from season or month of birth on the risk of developing MS in Sweden and Iceland. Information about month of birth, gender, and phenotype of MS for patients born 1940-1996 was retrieved from the Swedish MS registry (SMSR), and their place of birth was retrieved from the Swedish Total Population Registry (TPR). The corresponding information was retrieved from medical journals of Icelandic MS patients born 1981-1996. The control groups consisted of every person born in Sweden 1940-1996, their gender and county of birth (TPR), and in Iceland all persons born between 1981 and 1996 and their gender (Statistics Iceland). We calculated the expected number of MS patients born during each season and in every month and compared it with the observed number. Adjustments were made for gender, birth year, and county of birth. We included 12,020 Swedish and 108 Icelandic MS patients in the analyses. There was no significant difference between expected and observed MS births related to season or month of birth in Sweden or Iceland. This was even the results before adjustments were made for birth year and birth place. No significant differences were found in subgroup analyses including data of latitude of birth, gender, clinical phenotype, and MS onset of 30 years or less. Our results do not support the previously reported association between season or month of birth and MS risk. Analysis of birth place and birth year as possible confounding factors showed no major influence of them on the seasonal MS risk in Sweden and Iceland.
| S-EPMC5760596 | biostudies-literature
Project description:Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.
| S-EPMC2678928 | biostudies-literature
Project description:Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
| S-EPMC4495769 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified multiple causal genes associated with amyotrophic lateral sclerosis (ALS); however, the genetic architecture of ALS remains completely unknown and a large number of causal genes have yet been discovered. To full such gap in part, we implemented an integrative analysis of transcriptome-wide association study (TWAS) for ALS to prioritize causal genes with summary statistics from 80,610 European individuals and employed 13 GTEx brain tissues as reference transcriptome panels. The summary-level TWAS analysis with single brain tissue was first undertaken and then a flexible p-value combination strategy, called summary data-based Cauchy Aggregation TWAS (SCAT), was proposed to pool association signals from single-tissue TWAS analysis while protecting against highly positive correlation among tests. Extensive simulations demonstrated SCAT can produce well-calibrated p-value for the control of type I error and was often much more powerful to identify association signals across various scenarios compared with single-tissue TWAS analysis. Using SCAT, we replicated three ALS-associated genes (i.e., ATXN3, SCFD1, and C9orf72) identified in previous GWASs and discovered additional five genes (i.e., SLC9A8, FAM66D, TRIP11, JUP, and RP11-529H20.6) which were not reported before. Furthermore, we discovered the five associations were largely driven by genes themselves and thus might be new genes which were likely related to the risk of ALS. However, further investigations are warranted to verify these results and untangle the pathophysiological function of the genes in developing ALS.
| S-EPMC7714931 | biostudies-literature
Project description:ObjectiveTo compare the duration of birth hospitalization in mothers with multiple sclerosis (MS) and their newborns relative to the general population and to investigate the impact of MS-related clinical factors on the length of birth hospitalization stays.MethodsData from the British Columbia Perinatal Database Registry and the British Columbia MS database were linked in this retrospective cohort study. The duration of birth hospitalization in mothers with MS and their newborns (n = 432) were compared with a frequency-matched sample of the general population (n = 2,975) from 1998 to 2009. Clinical factors investigated included disease duration and disability, as measured by the Expanded Disability Status Scale. A multivariable model (generalized estimating equations) was used to analyze the association between MS and duration of birth hospitalization, adjusting for factors such as maternal age, diabetes, hypertension, and consecutive births to the same mother. Additional analyses included propensity score matching to further balance cohort characteristics.ResultsCompared with the general population, the duration of birth hospitalization was not statistically or clinically different for mothers with MS or their newborns (median differences = +1.5 and +2.1 hours, respectively; adjusted p > 0.4). Lengths of birth hospitalization were not significantly associated with disease duration (adjusted p > 0.7) or level of disability (adjusted p > 0.5). Findings remained virtually unchanged after propensity score matching.ConclusionsBirth hospitalization has been understudied in women with MS. Contrary to existing studies, we found that MS was not associated with a longer birth hospitalization. This study provides assurance to expectant mothers with MS, their families, and health care providers.
| S-EPMC3590045 | biostudies-literature