Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study.

OBJECTIVE: To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions. DESIGN: Population-based cohort study. SETTING: Linked UK maternal-child primary care records. POPULATION: A total of 349,127 singletons liveborn between 1990 and 2009. METHODS: Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression. MAIN OUTCOME MEASURES: Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups. RESULTS: Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6-2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5-3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2-3.2%) and 3.1% (95% CI 2.2-4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96-1.18), SSRIs (aOR 1.01, 95% CI 0.88-1.17), or TCAs (aOR 1.09, 95% CI 0.87-1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09-2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00-2.80). CONCLUSIONS: Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.

Classification: purposes, principles, progress, prospects.

There is an intimate interrelation between principles and procedures in classification, and modern work in this field has been profoundly affected by the development of electronic computers. Besides the delineation of natural systems and the achievement of economy of memory and ease of manipulation, the primary purpose of classification is the description of the structure and relationship of groups of similar objects. Successful classifications generate scientific hypotheses, although much classificatory work has applied, practical goals. The acceptance of polythetic taxa is a major conceptual advance and has directly led to classifications based on many, equally weighted characteristics. The specification of data for classification by computer will enhance objectivity but not eliminate cultural and subjective biases. Techniques of classification include cluster analysis and ordination, and numerous ways of representing classifications have been elaborated recently. By the application of graph theory to some classificatory problems it has been possible to reconstruct evolutionary branching sequences. Computer classification has been successfully applied across a broad range of disciplines.

Senescence and genetic load: evidence from Tribolium.

After 40 generations in which young adults were killed shortly after the onset of reproduction, strains of Tribolium castaneum with significantly decreased median longevity evolved. These findings support the hypothesis that the longevity of a species is controlled by genetic factors, and represents a compromise between selection for longer reproductive period and the limit set by environmental hazards.

A Test of Spatial Autocorrelation Analysis Using an Isolation-by-Distance Model.

Using the isolation-by-distance model as an example, we have examined several assumptions of spatial autocorrelation analysis applied to gene frequency surfaces. Gene frequency surfaces generated by a simulation of Wright's isolation-by-distance model were shown to exhibit spatial autocorrelation, except in the panmictic case. Identical stochastic generating processes result in surfaces with characteristics that are functions of the process parameters, such as parental vagility and neighborhood size. Differences in these parameters are detectable as differences in spatial autocorrelations after only a few generations of the simulations. Separate realizations of processes with identical parameters yield similar spatial correlograms. We have examined the inferences about population structure that could have been made from these observations if they had been real, rather than simulated, populations. From such inferences, we could have drawn conclusions about the presence of selection, migration and drift in given natural systems.

The survival of mutants at very low frequencies in tribolium populations.

Forty population cages, each with 499 adult T. castaneum of the wild-type UPF strain, received a bb female newly mated with UPF males. Half of the immigrants had a Chicago Black genetic background, the other half a UPF background. These conditions simulate, respectively, the fate of a rare, genetically differing immigrant or the fate of a mutation in populations of considerable size. Adults were censused for 11 discrete generations. The semi-dominant autosomal black gene survived in 26 out of 40 cultures by the end of the experiment, demonstrating its selective advantage at these very low frequencies. The gene increased from an initial frequency of 0.002 to 0.055 (at generation 11) in at least one replicate. Although frequency-dependent fitness has been shown for black at higher frequencies, no such dependence could be demonstrated at the low frequencies of this study. The cultures simulating mutations (immigrants with native backgrounds) had a higher average gene frequency, different distribution of gene frequencies across replicates, and a lower extinction rate of black than did the cultures with alien background immigrants. The observations only partially fitted expectation based on a branching process model. The data show a tendency for the persistence of a few heterozygotes in cultures and for a deficiency of cultures that lost the mutant or those with many heterozygotes. The increase in frequency of black cannot be attributed to increased reproductive success of heterozygotes. The advantage of heterozygotes appears due to delayed developmental period as a result of tactile stimulation and probable differential cannibalism among pupae.

The genetic structure of a tribal population, the Yanomama Indians. XV. Patterns inferred by autocorrelation analysis.

Fifteen allele frequencies have previously been determined for 50 villages of the Yanomama, an Amerindian tribe from southern Venezuela and northern Brazil. These frequencies were subjected to spatial autocorrelation analysis to investigate their population structure. There are significant spatial patterns for most allele frequencies. Clinical patterns, investigated by one-dimensional and directional spatial correlograms, were relatively few in number and were moderate in strength. Overall, however, there is a marked decline in genetic similarity with geographic distance. The results are compatible with a hierarchic population structure superimposed on the geography, and generated by a stochastic fission-fusion model of village propagation, followed by localized gene flow. Strong temporal autocorrelations of allele frequencies based on linguistic-historical distances representing time since divergence were also found. There appears to be a stronger relation between geography and linguistic-historical hierarchic subdivisions than between either feature and genetic distances. These findings confirm by different approaches the results of earlier analyses concerning the important roles of both stochastic and social factors in determining village allele frequencies and the occurrence within this tribe of some allele frequency clines most likely due to the operation of chance historical processes.

Spatial autocorrelation analysis of migration and selection.

We test various assumptions necessary for the interpretation of spatial autocorrelation analysis of gene frequency surfaces, using simulations of Wright's isolation-by-distance model with migration or selection superimposed. Increasing neighborhood size enhances spatial autocorrelation, which is reduced again for the largest neighborhood sizes. Spatial correlograms are independent of the mean gene frequency of the surface. Migration affects surfaces and correlograms when immigrant gene frequency differentials are substantial. Multiple directions of migration are reflected in the correlograms. Selection gradients yield clinal correlograms; other selection patterns are less clearly reflected in their correlograms. Sequential migration from different directions and at different gene frequencies can be disaggregated into component migration vectors by means of principal components analysis. This encourages analysis by such methods of gene frequency surfaces in nature. The empirical results of these findings lend support to the inference structure developed earlier for spatial autocorrelation analysis.

Ancient movement patterns determine modern genetic variances in Europe.

A summary ethnohistory database on population movements in Europe between 2000 B.C. and A.D. 1970 was related to genetic variances and distances based on 26 genetic systems. For the purposes of these analyses, Europe was divided into 85 terrestrial quadrats measuring 5 degrees x 5 degrees. Counts, stratified by time, were taken of the number of movements out of and into each quadrat (called source and target counts, respectively) and between each pair of quadrats. The source and target counts have distinct and different patterns in Europe and vary significantly over time. Central Europe and the Pontic area have the quadrats with the highest source counts, and the Balkans have the highest target counts. Modern genetic variances per quadrat are significantly correlated with source and target counts, somewhat more prominently with source counts. Genetic distances between pairs of quadrats are correlated strongly with geographic distances and moderately and negatively correlated with the total number of movements between these quadrats. Partial correlations of genetic distances with total number of movements, holding geographic distance constant, are small and mostly nonsignificant. These results are interpreted in light of our knowledge of the history and biology of the populations concerned.

Genetic, geographic, and linguistic distances in Europe.

Genetic and taxonomic distances were computed for 3466 samples of human populations in Europe based on 97 allele frequencies and 10 cranial variables. Since the actual samples employed differed among the genetic systems studied, the genetic distances were computed separately for each system, as were matrices of geographic distances and of linguistic distances based on membership in the same language family or phylum. Significant matrix correlations between genetics and geography were found for the majority of systems; somewhat less frequent are significant correlations between genetics and language. The effects of the two factors can be separated by means of partial matrix correlations. These show significant values for both genetics and geography, language kept constant, and genetics and language, geography kept constant, with a tendency for the former to be higher. These findings demonstrate that speakers of different language families in Europe differ genetically and that this difference remains even after geographic differentiation is allowed for. The greater effect of geography than of language may be due to the several factors that bring about spatial differentiation in human populations.

Geographic variation of six dermatoglyphic traits in Eurasia.

We describe the geographic variation patterns of six dermatoglyphic traits from 144 samples in Eurasia. The methods of analysis include computation of interpolated surfaces, one-dimensional and directional correlograms, correlations between all pairs of surfaces, and distances between correlograms. There are at least two, probably three, distinct and significant patterns of variation. 1) A general NW-SE trend for pattern intensity, the main line index, and frequency of hypothenar patterns. 2) A trend from the Middle East to the north and east for frequency of axial triradius and of accessory interdigital triradii. 3) A patchy pattern for frequency of the thenar-interdigital 1. The results are compatible with a diffusion process between Europe and the peoples of Northern Asia, and possibly with a radiation of populations from the Middle East. The hypothesis of diffusion processes is supported by substantial interpopulation correlations between dermatoglyphic traits that contrast sharply with largely negligible intralocality correlations.

Genetic structure of human populations in the British Isles.

Spatial patterns were studied for 36 allele frequencies representing 14 genetic systems (blood antigens, enzymes and serum proteins) in the United Kingdom and Irish Republic. The total number of data points over all systems and localities is 331. Patterns of genetic variation in space are graphically represented by one-dimensional and directional correlograms, and by interpolated allele-frequency surfaces. The data surfaces were examined by the various techniques of spatial autocorrelation analysis. Zones of rapid change across allele surfaces were discovered by the wombling method. Six allele frequency surfaces from four genetic systems exhibit significant spatial patterns. Only one pattern (IO; in the ABO system) may be described as purely clinal in an east-west direction; another (IB; in ABO) approximates a cline or at least north-south differentiation. A method was developed for testing the direction of maximal genetic autocorrelation. Two previously unrecorded patterns for the British Isles, north-south gradients for Rhesus and P, were detected. Twelve zones of rapid genetic change were discovered; some of these seem to reflect maritime and montane physical barriers as well as long-held cultural and linguistic differences, particularly between early Germanic and Celtic speakers. Moreover, some appear to reflect past historic events such as the invasions of Anglo-Saxons and Anglo-Normans.

Genetic population structure of Italy. II. Physical and cultural barriers to gene flow.

Three approaches were employed to evaluate the relative importance of geographic and linguistic factors in maintaining genetic differentiation of Italian populations as shown by blood groups and erythrocyte and serum markers. Genetic distances are closer to linguistic than to geographic distances. Gene-frequency change across 12 linguistic boundaries is significantly more rapid than at random locations. The zones of sharp genetic variation correspond to physical barriers to gene flow and to boundaries between dialect families, which overlap widely. However, two linguistically differentiated populations appear genetically differentiated despite the absence of physical obstacles to gene flow around them. The Po River is associated with abrupt genetic change only in the area where it corresponds to a dialect boundary. At most loci the genetic population structure seems affected by linguistic rather than geographic factors; exceptions are the systems that were subject to malarial selection in geographically close but linguistically heterogeneous localities. Gene flow appears to homogenize gene frequencies within regions corresponding to dialect families but not between them, leading to the patchy distributions of allele frequencies that were detected in an earlier study.

Genetic population structure of Italy. I. Geographic patterns of gene frequencies.

The diversity of spatial patterns of 61 allele frequencies for 20 genetic systems (15 loci) in Italy is presented. Blood antigens, enzymes, and proteins were analyzed. The total number of data points over all systems and localities was 1119. We used homogeneity tests, one-dimensional and directional spatial correlograms, and SYMAP interpolated surfaces. The data matrices were reduced by clustering techniques to reveal the principal patterns. Only a few allele frequency surfaces are strongly correlated across loci. All systems but one (ADA) exhibit significant heterogeneity in allele frequencies among the localities. Significant spatial patterns are shown by 27 of the 61 surfaces. Only one pattern (cde; system 4.19) is clinal; another (PGM1) exhibits a pure isolation by distance pattern; the others show long-range differentiation in addition to the short-distance decline of autocorrelation expected under isolation by distance. There is a marked decline in overall genetic similarity with distance for most variables. The 27 spatially significant alleles in Italy are also significantly patterned in Europe, but in all but 2 cases the country-wide and continent-wide patterns differ. The Italian patterns are due to forces specific to Italy. Differential selection for alleles associated with malaria is still evident. Whereas short-range differentiation can with malaria is still evident. Whereas short-range differentiation can be explained by isolation by distance, long-range differentiation appears to be due to demographic changes in certain populations that may be maintained by physical and linguistic isolation.

Origins of Indo-Europeans and the spread of agriculture in Europe: comparison of lexicostatistical and genetic evidence.

A series of tests was undertaken to relate lexicostatistical dissimilarities (LAN) among 48 Indo-European languages to distances representing various causal hypotheses. The comparison is limited to languages currently spoken in Europe. The putative causal distance matrices include (1) geographic (GEO) distances between the languages, (2) distances representing the origin of agriculture (OOA), (3) distances representing a model postulated by C. Renfrew (REN) concerning transformations that gave rise to the major Indo-European language families in Europe, and (4) distances representing a competing hypothesis by M. Gimbutas (GIM) concerning the origin and spread of Indo-European languages in Europe. Pairwise Mantel tests of the matrices show that OOA correlates better with LAN than does REN, supporting Renfrew's basic hypothesis of the dispersal of the Indo-European languages with the spread of agriculture but showing less effect for his postulated transformations. Partial correlation of LAN with OOA when GEO is held constant is significant at p = 0.004, whereas REN is no longer correlated with LAN when GEO is held constant. When repeated for only seven languages chosen to represent the seven major families of Indo-European languages currently spoken in Europe, the results differed appreciably, yielding a negative, albeit nonsignificant, partial correlation between OOA and LAN when GEO is held constant. This apparent contradiction led us to develop some new statistical approaches to examine, confirm, and explain the patterns. Decomposing the Mantel correlation coefficients for the 48 Indo-European languages into several additive correlation components showed that much of the positive component of the correlation coefficient was contributed by LAN, OOA correlation within language families, particularly within the Germanic family, covering up the negative contributions between language families. The differentiation of the seven major Indo-European language branches in Europe seems unrelated to the times of the origin of agriculture. This finding fails to support the fundamental assumption of Renfrew's hypothesis. There are also no significant correlations between LAN and REN or GIM. A series of Monte Carlo experiments confirmed these findings. Consideration of the accumulated evidence from genetics supports the model of demic diffusion during the origin of agriculture. However, published genetic studies and the present study lend no support to the notion that the early farmers were indeed the Indo-Europeans.

Classification of the European language families by genetic distance.

Genetic distances among speakers of the European language families were computed by using gene-frequency data for human blood group antigens, enzymes, and proteins of 26 genetic systems. Each system was represented by a different subset of 3369 localities across Europe. By subjecting the matrix of distances to numerical taxonomic procedures, we obtained a grouping of the language families of Europe by their genetic distances as contrasted with their linguistic relationships. The resulting classification largely reflects geographic propinquity rather than linguistic origins. This is evidence for the primary importance of short-range interdemic gene flow in shaping the modern gene pools of Europe. Yet, some language families--i.e., Basque, Finnic (including Lappish), and Semitic (Maltese)--have distant genetic relationships with their geographic neighbors. These results indicate that European gene pools still reflect the remote origins of some ethnic units subsumed by these major linguistic groups.

Cranial variation in European populations: a spatial autocorrelation study at three time periods.

This study reports on spatial variation of 10 cranial variables in European populations at 3 time periods. Means for these variables, based on 137, 108, and 183 samples from the Early Medieval, Late Medieval, and Recent periods, were subjected to one-dimensional and directional spatial autocorrelation analyses. Significant spatial structure was found for most variables. It becomes more pronounced as time progresses. The spatial patterns are not strongly clinal. Correlograms based on distances computed from all variables are monotonic only to 900, 1,650, and 1,350 km for the three periods. Regional patterns are seen for most variables and become more structured and significant with time. There is little similarity among the correlograms of the variables at any one period and virtually none among periods. Inferences about spatial structure of these populations, based on spatial autocorrelation analysis, suggest a pattern dominated by migration, followed by expansion and admixture rather than selection or chance fluctuations. The patterns of morphometric change seem to reflect the patterns of linguistic change in these areas.

Spatial genetic structure of human populations in Japan.

We studied spatial patterns for 24 allele frequencies representing 15 systems (blood antigens, enzymes, serum proteins, color blindness, and cerumen) in Japan. The total number of samples over all systems and localities is 1125. We investigated patterns of genetic variation graphically as interpolated allele frequency surfaces, as one-dimensional and directional correlograms, and by testing for the direction of maximal genetic autocorrelation. We examined the allele frequency surfaces by various techniques of spatial autocorrelation analysis and found 13 allele frequency surfaces from 9 genetic systems exhibiting significant spatial patterns. Several surfaces have clinal patterns along the major axis of the Japanese archipelago; others tend toward a maximum or minimum in south-central Honshu. Yet other allele frequencies show long-distance differentiation or patchiness. We discovered seven areas of rapid genetic change by using the wombling method. These areas largely reflect maritime and montane barriers, and some are associated with dialectal boundaries in these populations. The observed patterns support the hybridization or dual structure hypothesis for the peopling of Japan.