Effect of fertility on secondary sex ratio and twinning rate in Sweden, 1749-1870.

We analyzed the effect of total fertility rate (TFR) and crude birth rate (CBR) on the number of males per 100 females at birth, also called the secondary sex ratio (SR), and on the twinning rate (TWR). Earlier studies have noted regional variations in TWR and racial differences in the SR. Statistical analyses have shown that comparisons between SRs demand large data sets because random fluctuations in moderate data are marked. Consequently, reliable results presuppose national birth data. Here, we analyzed historical demographic data and their regional variations between counties in Sweden. We built spatial models for the TFR in 1860 and the CBR in 1751-1870, and as regressors we used geographical coordinates for the provincial capitals of the counties. For both variables, we obtained significant spatial variations, albeit of different patterns and power. The SR among the live-born in 1749-1869 and the TWR in 1751-1860 showed slight spatial variations. The influence of CBR and TFR on the SR and TWR was examined and statistical significant effects were found.

Repeated multiple maternities in triplet families.

In earlier studies, scientists have attempted to identify genetic and environmental factors affecting the rate of multiple maternities among humans. We contribute to these studies by analysing the frequencies of multiple maternities in sibships containing triplets. Use of the Hellin transformation is included in evaluation of the triplet rate. Our results indicate greater frequencies of repeated multiple maternities in the sibships than expected, based on population frequencies. The excesses obtained are more marked in triplet maternities than in twin maternities. The transformed triplet rate shows results similar to the twinning rate. The findings also indicate that in families, the influence of maternal factors on the frequencies of multiple maternities is stronger than the influence of paternal factors.

Birth weight among single and multiple births on the Åland islands.

Numerous papers have investigated the distribution of birth weight. This interest arises from the association between birth weight and the future health condition of the child. Birth weight distribution commonly differs slightly from the Gaussian distribution. The distribution is typically split into two components: a predominant Gaussian distribution and an unspecified 'residual' distribution. In this study, we consider birth weight data from the Åland Islands (Finland) for the period 1885-1998. We compare birth weight between males and females and among singletons and twins. Our study confirms that, on average, birth weight was highest among singletons, medium among twins, and lowest among triplets. A marked difference in the mean birth weight between singleton males and females was found. For singletons, the distribution of birth weight differed significantly from the normal distribution, but for twins the normal distribution held.

The international biological program/human adaptability studies among the Skolt Sami in Finland (1966-1970).

BACKGROUND: The population is increasingly lighter pigmented moving in a northward direction in Europe until reaching the Arctic Circle, where the Samis (Lapps) are clearly more pigmented. METHODS: In 1966-1970, we investigated a total of 689 subjects in the villages of Sevettijärvi and Nellim, including persons with mixed Sami and Finnish heritage; of these, 487 (242 males, 245 females) had both parents classified as Skolt Sami. For estimation of the colour of the iris and hair, international scales were used. For translucency of the iris, pigmentation of the fundus was estimated in 3 different shades. The length and type of eyelashes were classified into 3 categories. To our knowledge, a simultaneous study of the pigmentation of eyebrows, eyelashes and eye fundus at different ages has not previously been published. RESULTS: The age differences of iris colour were highly significant. Iris colour in children varied markedly, and they generally had lighter colours than later in life. Age and sex effects on the translucency of irises were found. Male irises were more translucent. Fundus pigmentation was scanty in the youngest age groups, with full pigmentation being reached at 20 years. Among young individuals hair colour darkens with increasing age. Eyebrow colour was slightly lighter for both sexes in the youngest age groups that in older cohorts. Women had longer eyelashes than males. CONCLUSIONS: The main factor of the lighter skin is a higher ability to synthesize vitamin D, providing superior protection against rickets. The Skolt Samis are more pigmented than other Nordic people. In earlier times they had problems with rickets but our studies did not show any essential symptoms of rickets today. Visual acuity among Skolt Samis was good. They had lower prevalence of myopia compared to Finns. The stronger pigmentation of Skolt Samis is probably due to their origin from darker Eastern populations. Since our investigations were made, the Skolt Samis have been to a great part mixed with neighbouring populations and scattered throughout Finland. Even their old language is nowadays used mainly for traditional purposes. Therefore similar studies could not be performed anymore.

Temporal trends in the secondary sex ratio in Nordic countries.

Attempts have been made to identify factors influencing the number of males per 100 females at birth, also called the secondary sex ratio. It has been proposed to vary inversely with the frequency of prenatal losses, but available data lend at best only weak support for this hypothesis. Statistical analyses have shown that comparisons between secondary sex ratios demand large data sets. Variations in the secondary sex ratio that have been reliably identified in family data have mostly been slight and without a notable influence on national birth registers. For Sweden, 1751-1950, the secondary sex ratio among all births and live births revealed increasing trends. The Swedish results are compared with available findings for live births in Finland, Norway, Denmark, and the small Icelandic population. For Norway and Denmark, the secondary sex ratio increased during 1801-1950. A similar, but stronger pattern was observed for Finland (1751-1950) and Iceland (1838-1950). During the latter half of the twentieth century, marked decreases were observed in all countries. Attempts to identify reliable associations between secondary sex ratios and stillbirth rates have been made, but no consistent results have emerged.

Secondary sex ratio in multiple births.

Attempts have been made to identify factors influencing the sex ratio at birth (number of males per 100 females). Statistical analyses have shown that comparisons between sex ratios demand large data sets. The secondary sex ratio has been believed to vary inversely with the frequency of prenatal losses. This hypothesis suggests that the ratio is highest among singletons, medium among twins and lowest among triplets. Birth data in Sweden for the period 1869-2004 showed that among live births the secondary sex ratio was on average 105.9 among singletons, 103.2 among twins and 99.1 among triplets. The secondary sex ratio among stillbirths for both singletons and twins started at a high level, around 130, in the 1860s, but approached live birth values in the 1990s. This trend is associated with the decrease and convergence of stillbirth rates among males and females. For detailed studies, we considered data for Sweden in 1869-1878 and in 1901-1967. Marital status or place of residence (urban or rural) had no marked influence on the secondary sex ratio among twins. For triplets, the sex ratio showed large random fluctuations and was on average low. During the period 1901-1967, 20 quadruplet, two quintuplet and one sextuplet set were registered. The sex ratio was low, around 92.0.

Spatial variation in the twinning rate in Sweden, 1751-1850.

Strong geographical variations in the twinning rate have been presented in the literature. In general, the rate is high among people of African origin, intermediate among Europeans and low among most Asiatic populations. In Europe, a progressive increase has occurred in the twinning rate from south to north, with a minimum around the Basque provinces. The highest twinning rates in Europe have been found among Nordic populations with the exception of the Saamis (Lapps). Within larger populations, some small isolated subpopulations have been identified to have extreme, mainly high, twinning rates. In this study, we investigated the regional variation of the twinning rate in Sweden. We analysed twinning rates for different counties for the period 1751-1850. From the middle of the 19th century, the environmental and genetic differences have decreased and the regional twinning rates have converged towards a common decreased level. The models applied have the geographical coordinates as regressors. The optimal model for the twinning rate has the longitude, the latitude and their product as regressors, indicating both horizontal and vertical trends. According to this model, the maximum twinning rate in Sweden is located in the eastern part of central Sweden, mainly on the island of Gotland and in the counties around Stockholm. Relatively low twinning rates are seen in the western and northern parts of Sweden.

Temporal and regional variations in the seasonality of births in Aland (Finland), 1653-1950.

Monthly numbers of births are influenced by the length of the month and, thus, rates per day should be used. Comparisons of seasonality in data sets of different sizes must be based on standardized indices. Although strong seasonality exists, a poor model may incorrectly yield low seasonality measures. The standard deviation of the inter-monthly variation in the indices has been used as a seasonality measure. We introduce a new measure based on analysis of variance (ANOVA). Our methods are applied on 107,896 births in the archipelago of Aland (Finland), 1653-1950. For all subregions, the birth indices for the period 1653-1850 showed marked peaks in March to April and in September to October. The seasonality is weakest for the Main Island and strongest for the most isolated parish, Kökar, which has many local/extreme socioeconomics and genetic characteristics. For the period 1851-1950, the seasonality disappeared almost totally. The variation in the seasonality between subregions can mainly be explained by socioeconomic differences, and the temporal decrease in all regions seems to be connected to diminishing differences in living conditions. Comparisons with data from Sweden and Finland show higher seasonality in Aland.

On the history of Hellin's law.

Theorems, proofs, laws and rules are commonly named according to the presumed investigator, but often earlier investigators have contributed substantially to the findings. One example of this is Hellin's law, which was named after Hellin, although he was not the first to discover it. In research on twinning and higher multiple maternities, the law has played a central role because it is approximately correct, despite showing discrepancies that are difficult to explain or eliminate. Several improvements to this law have been proposed. In this study, we re-examine some old papers to provide an overview of the scientists who have contributed to the genesis and the improvements of this law. In addition, we consider more recent contributions in which Hellin's law has been discussed and evaluated. It has been mathematically proven that Hellin's law does not hold as a general rule. However, most studies are based on empirical rates of multiple maternities, ignoring random errors. Such studies can never confirm the law, but only serve to identify errors too large to be characterized as random.

Statistical analyses of Hellin's law.

During the history of research on multiple maternities, Hellin's law has played a central role as a rule of thumb. It is mathematically simple and approximately correct, but shows discrepancies that are difficult to explain or to eliminate. It has been mathematically proven that Hellin's law does not hold as a general rule. Varying improvements to this law have been proposed. In this paper, we consider how Hellin's law can be used and tested in statistical analyses of the rates of multiple maternities. Such studies can never confirm the law, but only identify errors too large to be characterized as random. It is of particular interest to determine why the rates of higher multiple maternities are sometimes too high or too low when Hellin's law is used as a benchmark. Excesses of triplet and quadruplet maternities are particularly unexpected and challenging. Our analyses of triplet and quadruplet rates indicated that triplet rates are closer to Hellin's law than quadruplet rates. According to our analyses of the twinning rate and the transformed triplet rate and quadruplet rate for Sweden (1751-2000), both triplet and quadruplet rates showed excesses after the 1960s. This is mainly caused by artificial fertility-enhancing reproduction technologies. Regression analyses of twinning and triplet rates yield rather good fits, but deficiencies in the triplet rates are commonly present. We introduced measures of concordance between triplet rates with Hellin's law. According to these measures, historic data showed deficiencies in triplet rates, but recent data revealed excesses, especially found among older mothers. The excesses obtained are in good agreement with other studies of recent data.

Association of LOXL1 gene with Finnish exfoliation syndrome patients.

In this study, three single-nucleotide polymorphisms (SNPs) on the lysyl oxidase-like 1 (LOXL1) gene associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) were investigated in the Finnish population. A case-control study of 59 sporadic patients with XFS, 82 with XFG, 71 with primary open-angle glaucoma (POAG) and 26 individuals without these disorders from the southern Finnish population, and a family study of an extended family with 28 patients with XFS or XFG and 92 unaffected relatives from Kökar islands, Southwestern Finnish archipelago, were conducted. Anonymous blood donors (n=404) were studied as population-based controls. Three SNPs, rs1048661 (R141L), rs3825942 (G153D) and rs2165241, of the LOXL1 gene were genotyped by PCR sequencing. Association and linkage analyses were carried out. In both case-control and family materials, significant association for allele G of rs1048661 (P=2.65 x 10(-5); P=0.0007), allele G of rs3825942 (P=2.24 x 10(-8); P=0.49) and allele T of rs2165241 (P=2.62 x 10(-13); P<0.0001) was found in XFS/XFG. However, linkage was not observed for LOXL1 risk alleles. The corresponding three-locus haplotype GGT increased the risk of XFS/ XFG nearly 15-fold relative to low-risk haplotype GAC (odds ratio (OR): 14.9, P=1.6 x 10(-16)). In conclusion, the earlier reported polymorphisms of the LOXL1 gene showed significant association also in the Finnish population.

Maternal age and temporal effects on stillbirth rates.

Stillbirth rates among single and multiple births show markedly decreasing temporal trends. In addition, several studies have demonstrated that the stillbirth rates are dependent on maternal age, in general, showing a U- or J-shaped association with maternal age. In this study, the temporal trends in and the effect of maternal age on the stillbirth rate were considered simultaneously. Our goal was to split the variation into temporal trends and maternal age effects. We applied two-dimensional analysis of variance because no linear association between maternal age and stillbirth rate can be assumed. The temporal trends of stillbirth rates also were not clearly linear. However, the possibility of applying regression analyses based on linear time trends was also considered. Our study is mainly based on official data from England and Wales for the period between 1927 and 2004. These results were compared with registered birth data from Finland between 1937 and 1997. The best fit was obtained when the models were built for the logarithm of the stillbirth rate. Our interpretation of this result is that an association exists between the effects of the factors and the mean stillbirth rate, and consequently, a multiplicative model was applied. Relatively high stillbirth rates were observed among twin births of young mothers and among all births of older mothers.

Temporal, seasonal, and regional differences in births and deaths in Aland (Finland).

A good knowledge of the seasonal variation during normal years is of fundamental importance for analyses of the effects of wars, famines, epidemics, or similar privations on births and deaths. In this study we consider data from the Aland Islands (Finland) for 1650-1950. During the period 1650-1793 there are subperiods with missing data for all parishes, and consequently the total data for the Aland Islands for this period have to be estimated using available data. For the period 1794-1950 the registered data seem to be complete and reliable, but the war year 1809 shows a marked deficit of births. During the last decades of the 19th century the number of births increases markedly and after that shows a strong decrease. After the 1930s births increase again. To allow seasonality comparisons between the Aland Islands as a whole and its subregions, we base our studies on seasonal indexes. There is a markedly decreasing temporal trend in the seasonal variation of births for the Aland Islands as a whole, but the general pattern remains mainly the same, having two peaks, one in March-April and one in September-October. For the period 1901-1950 the seasonal variation almost disappeared. The strength of the seasonal variation in births shows regional differences, but the general pattern is mainly the same. The outermost parish, Kökar, an isolate of its own, shows the strongest seasonal variation in births. The annual number of deaths shows some marked peaks, especially in the war year 1809. For both sexes there are marked peaks in 1809, indicating that the deaths were mainly caused by epidemic diseases rather than by killing in battles. For mortality a decreasing trend in the seasonal variation is observed during 1650-1750, but after 1751-1800 the strength of seasonality shows an increasing trend and a sinusoidal pattern.

Correlations between live and stillbirth outcomes in twin pairs.

A relationship has been proposed to exist between individual outcomes (live or stillbirth) of twins in the same set. Here, we analyze this association between live births and stillbirths among individuals in different twin pairs. When national birth registers are analyzed, individuals in opposite-sex twin sets can be identified and the correlation between individual outcomes estimated. However, full information about the individuals in same-sex twin sets is not, as a rule, available, and consequently, correlation coefficients cannot be estimated, but upper and lower limits of the correlation coefficients can be obtained. The methods introduced here were applied to data from Sweden (1869-1967), the Aland Islands (Finland) (1750-1949), the Kingdom of Saxony (1881-1900), and England and Wales (1940-2003). Comparisons between the correlation coefficients among opposite-sex twins and the lower bound (minimum) of correlation coefficients among same-sex twins indicate that in all populations studied a stronger association exists between twins in same-sex rather than opposite-sex twin sets or pairs. For opposite-sex twin sets no general association between the correlation coefficient and the stillbirth rate was identified.

Sex ratio in sibships with twins.

In national birth registers of Caucasians, the secondary sex ratio, that is, the number of boys per 100 girls at birth, is almost constant at 106. Variations other than random variation have been noted, and attention is being paid to identifying presumptive influential factors. Studies of the influence of different factors have, however, yielded meagre results. An effective means of identifying discrepancies is to investigate birth data compiled into sibships of different sizes. Assuming no inter- or intra-maternal variations, the distributions of the sex composition are binomial. Varying parental tendencies for a specific sex result in discrepancies from the binomial distribution. Over a century ago, the German scientists Geissler and Lommatzsch analyzed the vital statistics of Saxony, including twin maternities, for the last quarter of the 19th century. They considered sibships ending with twin sets. Their hypothesis was that in sibships ending with male-male twin pairs, the sex ratio among previous births is higher than normal, while in sibships with female-female twin pairs, the sex ratio is lower than normal. If the sibship ended with a male-female pair, then the sex ratio is almost normal. Consequently, a same-sex twin set indicated, in general, deviations in the sex ratio among the sibs within the sibship. Our analyzes of their data yielded statistically significant results that support their statements.

Genome-wide scan of exfoliation syndrome.

PURPOSE: Exfoliation syndrome (XFS) is an age-related ocular condition that is characterized by the accumulation of fibrillogranular extracellular material in intra- and extraocular tissues. The purpose of the present study was to identify the genetic basis of XFS in a large Finnish family. METHODS: A genome-wide scan with 1000 microsatellite markers was performed in an extended family from an island in the southwestern Finnish archipelago where XFS demonstrates an autosomal dominant mode of inheritance with incomplete penetrance. Two-point linkage analyses were performed with MLINK and multipoint linkage, using the Vitesse program. RESULTS: Five chromosomal regions with markers showing two-point LOD scores more than 1.5 was identified by using a dominant mode of inheritance for the XFS trait. The most promising locus was assigned to 18q12.1-21.33 with a maximum two-point LOD score of 3.45 and a multipoint LOD score of 4.2. Some evidence of linkage was obtained at chromosomes 2q, 17p, and 19q, which were suggested in earlier reports to be possible regions of linkage to primary open-angle glaucoma (POAG). CONCLUSIONS: The study presented herein offers a starting point to unravel the molecular background of XFS.

Temporal trends in the rates of multiple maternities in England and Wales.

After a long continuous decrease, the twinning and higher multifetal rates in many developed countries have increased during the last 2 to 3 decades. This change has been attributed to delayed childbearing and to increased use of subfertility treatments, particularly in women over 35 years of age. In this study we analyze how these new trends depend on changes in the effect of maternal age on the rates of multiple maternities. Our study is based on data for England and Wales for the period 1938 to 2003. The temporal variations show a decreasing trend to a trough around 1980 and after that a steady increase. This increase was more marked for higher multifetal rates and was particularly high for quadruplets. Furthermore, we identified changes in the age-specific rates resulting in increased levels for older mothers. These findings are in good agreement with our results from Nordic populations.

Exfoliation syndrome: prevalence and inheritance in a subisolate of the Finnish population.

PURPOSE: To estimate the prevalence of pseudoexfoliation syndrome or exfoliation syndrome (ES) in a cross-sectional study and during a long-term follow-up, and to analyse how ES has been inherited in a large pedigree on an isolated population of Kökar island in southern Finland. METHODS: In a population-based study conducted between 1960 and 1962, a comprehensive ophthalmological examination was performed on 595 subjects (85% of the population). From then until 2002, 965 subjects were examined at least once. A pedigree was constructed for all ES-affected subjects according to genealogical studies. The genetic contribution to ES was investigated in this pedigree by segregation analysis and the heritability of the intraocular pressure (IOP) quantitative trait estimated using SOLAR and SAGE software. RESULTS: In the cross-sectional study, the prevalence of ES was 8.1% for 247 subjects over 50 years of age (males 7%, females 9%) and increased to 18.4% for 70 subjects over 70 years of age (males 13%, females 25%). In addition, two females less than 50 years of age were ES-affected. Between 1960 and 2002, 76 (14.3%) of 530 subjects over 50 years of age had ES [23 males (10%) and 53 females (18%)]. Exfoliation glaucoma (EG) was found more often in males (11 patients, 48%) than in females (13 patients, 25%) whereas primary open-angle glaucoma (POAG) was almost as frequent in males (seven patients, 3%) as in females (five patients, 2%). The relative risk (RR) of glaucoma (ES versus no ES) was 11.9 [95% confidence interval (CI) 6.2-22.9] for all the subjects - 14.6 for males (95% CI 6.3-34.0) and 11.8 for females (95% CI 4.4-31.6). Seventy-five pedigrees of 78 ES-affected patients were linked together into one large pedigree with 110 nuclear families. The segregation ratio of ES was 18% (8% for males, 24% for females) when both parents were unaffected, and 16% (9% for males, 27% for females) when at least one parent was affected. The heritability of IOP was estimated to be 30%. CONCLUSION: In this population-based family study, ES is consistent with an autosomal dominant trait with incomplete penetrance, where the penetrance is more reduced in males than in females. However, the presence of ES was a greater risk factor for developing glaucoma in males than in females.

Estimation of the stillbirth rate in twin pairs according to zygosity.

It is common opinion that the stillbirth rate is higher among monozygotic (MZ) than among dizygotic (DZ) twins. This is supported by the fact that stillbirth rates are higher among same-sexed than among opposite-sexed twins, and the relatively high stillbirth rates among twins of young mothers. In this study we present a method to estimate the stillbirth rates for MZ and DZ twins and identify the difference. We performed analyses based on the assumptions of (a) Weinberg's differential rule, including the assumption that the secondary sex ratio is 100, (b) the stillbirth rates among opposite-sexed twins hold for all DZ twins, and (c) the stillbirth rates estimated for MZ and DZ male and female twins yield for both sexes the observed total number of stillborn twins. Our methods are applied to data from Sweden, 1869-1967, the Aland Islands, 1750-1949, Saxony, 1881-1900, and England and Wales, 1996-2003. We observed that the ratio between the estimated stillbirth rates among MZ and DZ twins were on average 1.75, and the ratio among same-sexed and DZ (opposite-sexed) twins were on average 1.31. For Sweden and Saxony similar values were obtained, but for England and Wales the values were higher and for Aland lower. With exception of Aland, the estimated stillbirth rates were in all populations the lowest for DZ, medium for same-sexed and highest for MZ twins.

Stillbirths in multiple births: test of independence.

The stillbirth rate in twins is a more sensitive indicator of environmental hazards than the stillbirth rate in singletons. Medical care or other socioeconomic factors may be more influential for perinatal survival in twin than in single deliveries. Studies have indicated that stillbirths among children in a set of multiple maternities are not independent. Models were considered assuming independent outcomes within a set of multiple maternities. Analyses of the stillbirth rates confirm that the risk of stillbirth among males is almost constantly higher than among females. Any model introduced should assume different stillbirth rates for males and females. The models were tested with both maximum likelihood and minimum chi2 methods. Data was analyzed from Sweden, the Aland Islands, Saxony, England and Wales, and significant discrepancies obtained from the independence models. The same-sexed twin data contain both monozygotic and dizygotic twin sets with apparently different stillbirth rates. Consequently, for same-sexed twins the proposed model could be considered too simple. After improvement by splitting the same-sexed data into monozygotic and dizygotic twin sets, the dependence still remains. The proportion of both same-sexed and opposite-sexed twin pairs that contain two stillborn is greater than what the stillbirth rates and the independence should indicate. Consequently, stillbirth rate estimates based on the relative frequency of twin sets with two stillborn children have a positive bias. When the stillbirth rate decreases, the number of sets with two stillborn children decreases more slowly than would be indicated by independence.