Comorbidities, bone-sparing agent prescription history and their determinants among postmenopausal women in UK primary care settings: a retrospective database study.

SUMMARY: Distinguishing oral bisphosphonates from other bone-sparing therapies, this retrospective observational study, first, characterized treated osteoporosis patients in the UK, and secondly, explored factors associated with the risk of discontinuation or switching between therapies. The latter should be considered when evaluating real-world data. PURPOSE: This retrospective observational study evaluated the characteristics of women with postmenopausal osteoporosis, including comorbidities and determinants of treatment patterns with bone-sparing agents. METHODS: The UK Clinical Practice Research Datalink was used to identify postmenopausal women (aged ≥50 years) treated with a bone-sparing agent or diagnosed with osteoporosis between 1 January 1993 and 31 December 2008. Two non-mutually-exclusive subpopulations were defined: (1) patients active in the database on 31 December 2008; (2) patients treated with a bone-sparing agent since 1 January 1993. Subpopulation 1 was used to describe patient comorbidities and osteoporosis treatment history, and subpopulation 2 was used to explore the characteristics associated with bone-sparing treatment patterns use via multivariable regression for repeated multinomial responses. RESULTS: A total of 62,657 individuals met the inclusion criteria; subpopulation 1 comprised 38,469 women (61.4%), of whom 21,687 received a bone-sparing agent in 2008 (99.7% oral bisphosphonates and the remainder other agents). Those receiving other agents were more likely to have had previous treatment with bone-sparing agents, to have experienced previous fractures, and to have visited their doctor more frequently. Analyses also identified several comorbidities associated with an increased risk of discontinuation of bone-sparing agents, including heart disease, gastrointestinal disease, and renal failure. Anticonvulsant use was associated with a dramatic increase in the risk of switching. CONCLUSIONS: Several patient characteristics were associated with discontinuation of, or switching between, bone-sparing treatments. Patients receiving bone-sparing medication other than oral bisphosphonates were more likely to have comorbid conditions and a history of fracture and to have taken an oral bisphosphonate previously.

Organic food consumption and the incidence of cancer in a large prospective study of women in the United Kingdom.

BACKGROUND: Organically produced foods are less likely than conventionally produced foods to contain pesticide residues. METHODS: We examined the hypothesis that eating organic food may reduce the risk of soft tissue sarcoma, breast cancer, non-Hodgkin lymphoma and other common cancers in a large prospective study of 623 080 middle-aged UK women. Women reported their consumption of organic food and were followed for cancer incidence over the next 9.3 years. Cox regression models were used to estimate adjusted relative risks for cancer incidence by the reported frequency of consumption of organic foods. RESULTS: At baseline, 30%, 63% and 7% of women reported never, sometimes, or usually/always eating organic food, respectively. Consumption of organic food was not associated with a reduction in the incidence of all cancer (n=53 769 cases in total) (RR for usually/always vs never=1.03, 95% confidence interval (CI): 0.99-1.07), soft tissue sarcoma (RR=1.37, 95% CI: 0.82-2.27), or breast cancer (RR=1.09, 95% CI: 1.02-1.15), but was associated for non-Hodgkin lymphoma (RR=0.79, 95% CI: 0.65-0.96). CONCLUSIONS: In this large prospective study there was little or no decrease in the incidence of cancer associated with consumption of organic food, except possibly for non-Hodgkin lymphoma.

Reproductive factors and risk of oesophageal and gastric cancer in the Million Women Study cohort.

BACKGROUND: Hormonal factors may influence risk for upper gastrointestinal cancers in women. We examined risk of oesophageal and gastric cancers in relation to reproductive factors in a large UK cohort, the Million Women Study. METHODS: Among 1,319,409 women aged on average 56 years at recruitment, 1186 incident cancers of the oesophagus and 1194 of the stomach were registered during 11.9 million person-years' observation. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: Risks of both oesophageal and gastric cancer were significantly higher in postmenopausal than in pre- or peri-menopausal women (RRs 1.46, 1.07-2.00 and 1.59, 1.15-2.20, respectively; P≤0.01 for both); and, among postmenopausal women, risk was higher the younger women were at menopause (RR, 95% CI per 5 years younger at menopause 1.18, 1.05-1.34 for oesophageal cancer and 1.18, 1.04-1.34 for stomach cancer, P(trend)=0.01 for both). For factors relating to childbearing, including women's age at first birth, their number of children, and breastfeeding history, the only significant association was a higher risk of oesophageal cancer in nulliparous, compared with parous, women (RR 1.31, 1.11-1.55; P=0.002). When risks for squamous cell and adenocarcinomas of the oesophagus were compared, most did not differ significantly, but statistical power was limited. CONCLUSION: Both oesophageal and gastric cancer risks appeared to be related to menopausal status and age at menopause, but there was little consistent evidence for associations with factors related to childbearing.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

OBJECTIVE: To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study. METHODS: Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. RESULTS: During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. CONCLUSION: We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.

A bivariate measurement error model for nitrogen and potassium intakes to evaluate the performance of regression calibration in the European Prospective Investigation into Cancer and Nutrition study.

OBJECTIVES: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, the performance of 24-h dietary recall (24-HDR) measurements as reference measurements in a linear regression calibration model is evaluated critically at the individual (within-centre) and aggregate (between-centre) levels by using unbiased estimates of urinary measurements of nitrogen and potassium intakes. METHODS: Between 1995 and 1999, 1072 study subjects (59% women) from 12 EPIC centres volunteered to collect 24-h urine samples. Log-transformed questionnaire, 24-HDR and urinary measurements of nitrogen and potassium intakes were analysed in a multivariate measurement error model to estimate the validity of coefficients and error correlations in self-reported dietary measurements. In parallel, correlations between means of 24-HDR and urinary measurements were computed. Linear regression calibration models were used to estimate the regression dilution (attenuation) factors. RESULTS: After adjustment for sex, centre, age, body mass index and height, the validity coefficients for 24-HDRs were 0.285 (95% confidence interval: 0.194, 0.367) and 0.371 (0.291, 0.446) for nitrogen and potassium intakes, respectively. The attenuation factors estimated in a linear regression calibration model were 0.368 (0.228, 0.508) for nitrogen and 0.500 (0.361, 0.639) for potassium intakes; only the former was different from the estimate obtained using urinary measurements in the measurement error model. The aggregate-level correlation coefficients between means of urinary and 24-HDR measurements were 0.838 (0.637, 0.932) and 0.756 (0.481, 0.895) for nitrogen and potassium intakes, respectively. CONCLUSIONS: This study suggests that 24-HDRs can be used as reference measurements at the individual and aggregate levels for potassium intake, whereas, for nitrogen intake, good performance is observed for between-centre calibration, but some limitations are apparent at the individual level.

Plasma phyto-oestrogens and prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

We examined plasma concentrations of phyto-oestrogens in relation to risk for subsequent prostate cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. Concentrations of isoflavones genistein, daidzein and equol, and that of lignans enterolactone and enterodiol, were measured in plasma samples for 950 prostate cancer cases and 1042 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of these phyto-oestrogens were estimated by conditional logistic regression. Higher plasma concentrations of genistein were associated with lower risk of prostate cancer: RR among men in the highest vs the lowest fifth, 0.71 (95% confidence interval (CI) 0.53-0.96, P trend=0.03). After adjustment for potential confounders this RR was 0.74 (95% CI 0.54-1.00, P trend=0.05). No statistically significant associations were observed for circulating concentrations of daidzein, equol, enterolactone or enterodiol in relation to overall risk for prostate cancer. There was no evidence of heterogeneity in these results by age at blood collection or country of recruitment, nor by cancer stage or grade. These results suggest that higher concentrations of circulating genistein may reduce the risk of prostate cancer but do not support an association with plasma lignans.

Reproductive history, hormonal factors and the incidence of hip and knee replacement for osteoarthritis in middle-aged women.

OBJECTIVES: To examine the effect of reproductive history and use of hormonal therapies on the risk of hip and knee joint replacement for osteoarthritis. METHODS: A prospective study of 1.3 million women aged on average 56 years at recruitment and followed-up through linkage to routinely collected hospital admission records was conducted. The adjusted relative risk (RR) of hip and knee replacement for osteoarthritis was examined in relation to parity, age at menarche, menopausal status, age at menopause and use of hormonal therapies. RESULTS: Over a mean of 6.1 person-years of follow-up, 12 124 women had a hip replacement and 9977 a knee replacement. The risk of joint replacement increased with increasing parity and the effect was greater for the knee than the hip: increase in RR of 2% (95% CI 1 to 4%) per birth for hip replacement and 8% (95% CI 6 to 10%) for knee replacement. An early age at menarche slightly increased the risk of hip and knee replacement (relative risk for menarche < or =11 years versus 12 years, 1.09 (95% CI 1.03 to 1.16) and 1.15 (95% CI 1.08 to 1.22), respectively). Menopausal status and age at menopause were not clearly associated with risk. Current use of postmenopausal hormone therapy was associated with a significant increase in the incidence of hip and knee replacement (RR 1.38 (95% CI 1.30 to 1.46) and RR 1.58 (95% CI 1.48 to 1.69), respectively) while previous use of oral contraceptives was not (RR 1.02 (95% CI 0.98 to 1.06) and RR 1.00 (95% CI 0.96 to 1.04) for hip and knee, respectively). CONCLUSIONS: Hormonal and reproductive factors affect the risk of hip and knee replacement, more so for the knee than the hip. The reasons for this are unclear.

Interleukin-1 promoter region polymorphism role in rheumatoid arthritis: a meta-analysis of IL-1B-511A/G variant reveals association with rheumatoid arthritis.

OBJECTIVES: IL-1 has a central role mediating inflammation and joint destruction in RA. Single nucleotide polymorphisms (SNPs) and haplotype structure in the promoter region can modulate IL-1 function. This study examined the effects of four common promoter SNPs in the IL-1 region on susceptibility and clinical characteristics of RA in British Caucasian patients and assessed the risk of RA by meta-analysis of published studies. METHODS: Using PCR-based methods, 756 RA patients and 625 healthy controls (HCs) were genotyped for IL-1A (-889 C/A, rs17561), IL-1B (-511 A/G, rs16944), IL-1B (-1464 C/G, rs1143623) and IL-1B (-3737 G/A, rs4848306) SNPs. Further meta-analysis was performed for IL-1B (-511 A/G) incorporating 3712 RA patients and 2331 HC from six association studies. RESULTS: The IL-1B (-1464 C/G) G allele was found to be less common in the RA group [P = 0.01; odds ratio (OR) 1.24; 95% CI 1.04, 1.48]. There was no association between IL-1 SNPs and the presence of HLA-DRB1 shared epitope, RF or clinical characteristics. Meta-analysis revealed statistically significant association between IL-1B (-511 A/G) and RA (P = 0.02; pooled OR 1.13; 95% CI 1.02, 1.26). CONCLUSIONS: There may be a protective effect in RA from the IL-1B (-1464 C/G) G variant. No direct association between the polymorphisms studied and clinical severity characteristics were observed. Further meta-analysis revealed IL-1B (-511 A/G) to be associated with increased susceptibility to RA.

Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition.

We examined consumption of animal foods, protein and calcium in relation to risk of prostate cancer among 142 251 men in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by recruitment centre and adjusted for height, weight, education, marital status and energy intake. After an average of 8.7 years of follow-up, there were 2727 incident cases of prostate cancer, of which 1131 were known to be localised and 541 advanced-stage disease. A high intake of dairy protein was associated with an increased risk, with a hazard ratio for the top versus the bottom fifth of intake of 1.22 (95% confidence interval (CI): 1.07-1.41, P(trend)=0.02). After calibration to allow for measurement error, we estimated that a 35-g day(-1) increase in consumption of dairy protein was associated with an increase in the risk of prostate cancer of 32% (95% CI: 1-72%, P(trend)=0.04). Calcium from dairy products was also positively associated with risk, but not calcium from other foods. The results support the hypothesis that a high intake of protein or calcium from dairy products may increase the risk for prostate cancer.

Active and passive smoking and the risk of breast cancer in women aged 36-45 years: a population based case-control study in the UK.

Active smoking has little or no effect on breast cancer risk but some investigators have suggested that passive smoking and its interaction with active smoking may be associated with an increased risk. In a population based case-control study of breast cancer in women aged 36-45 years at diagnosis, information on active smoking, passive smoking in the home, and other factors, was collected at interview from 639 cases and 640 controls. Women were categorised jointly by their active and passive smoking exposure. Among never smoking controls, women who also reported no passive smoking exposure were significantly more likely to be nulliparous and to be recent users of oral contraceptives. Among those never exposed to passive smoking, there was no significant association between active smoking and breast cancer, relative risk (RR) of 1.12 (95% confidence interval (CI) 0.72-1.73) for past smokers and RR of 1.19 (95% CI 0.72-1.95) for current smokers, nor was there an association with age started, duration or intensity of active smoking. Compared with women who were never active nor passive smokers, there was no significant association between passive smoking in the home and breast cancer risk in never smokers, RR of 0.89 (95% CI 0.64-1.25), in past smokers, RR of 1.09 (95% CI 0.75-1.56), or in current smokers, RR of 0.93 (95% CI 0.67-1.30). There was no trend with increasing duration of passive smoking and there was no heterogeneity among any of the subgroups examined. In this study, there was no evidence of an association between either active smoking or passive smoking in the home and risk of breast cancer.

Comparative fracture risk in vegetarians and nonvegetarians in EPIC-Oxford.

OBJECTIVE: To compare fracture rates in four diet groups (meat eaters, fish eaters, vegetarians and vegans) in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). DESIGN: Prospective cohort study of self-reported fracture risk at follow-up. SETTING: The United Kingdom. SUBJECTS: A total of 7947 men and 26,749 women aged 20-89 years, including 19,249 meat eaters, 4901 fish eaters, 9420 vegetarians and 1126 vegans, recruited by postal methods and through general practice surgeries. METHODS: Cox regression. RESULTS: Over an average of 5.2 years of follow-up, 343 men and 1555 women reported one or more fractures. Compared with meat eaters, fracture incidence rate ratios in men and women combined adjusted for sex, age and non-dietary factors were 1.01 (95% CI 0.88-1.17) for fish eaters, 1.00 (0.89-1.13) for vegetarians and 1.30 (1.02-1.66) for vegans. After further adjustment for dietary energy and calcium intake the incidence rate ratio among vegans compared with meat eaters was 1.15 (0.89-1.49). Among subjects consuming at least 525 mg/day calcium the corresponding incidence rate ratios were 1.05 (0.90-1.21) for fish eaters, 1.02 (0.90-1.15) for vegetarians and 1.00 (0.69-1.44) for vegans. CONCLUSIONS: In this population, fracture risk was similar for meat eaters, fish eaters and vegetarians. The higher fracture risk in the vegans appeared to be a consequence of their considerably lower mean calcium intake. An adequate calcium intake is essential for bone health, irrespective of dietary preferences. SPONSORSHIP: The EPIC-Oxford study is supported by The Medical Research Council and Cancer Research UK.

Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis.

We conducted a systematic review of the risk of pancreatic cancer in people with type I and young-onset diabetes. In three cohort and six case-control studies, the relative risk for pancreatic cancer in people with (vs without) diabetes was 2.00 (95% confidence interval 1.37-3.01) based on 39 cases with diabetes.

Body fatness and physical activity at young ages and the risk of breast cancer in premenopausal women.

We examined the relationship between body fatness, sports participation and breast cancer risk in 1560 premenopausal cases and 1548 controls, from three related population-based case-control studies in the UK. Half of the women with breast cancer were aged less than 36 years at diagnosis. Women who perceived themselves as plump at age 10 years had a relative risk of 0.83 (95% confidence interval 0.69-0.99, P = 0.03) as compared with those who perceived themselves as thin. Self-reported obesity compared with leanness at diagnosis was associated with a relative risk of 0.78 (95% confidence interval 0.56-1.06, P = 0.11). Women who reported having been plump at age 10 years and overweight or obese at diagnosis had a relative risk of 0.75 (95% confidence interval 0.56-1.01, P = 0.06) as compared with those who reported being thin at age 10 years and at diagnosis. Findings for three related measures of body fatness suggested that obesity is associated with a reduced risk of premenopausal breast cancer. There was no association between sports participation and breast cancer risk in these premenopausal women. The relative risk for spending an average of more than 1 h per week in sports compared with less from ages 12 to 30 years was 1.00 (95% CI 0.86-1.16, P = 0.98).

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk.

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

On the calculation of intestinal schistosome infection intensity.

The effects of using different methods to calculate individual infection intensities on the age-infection distribution of Schistosoma mansoni field data are demonstrated. Methods are tested on a maximum of three stool samples per person collected on three consecutive days; the methods considered for the calculation of individual infection intensities are the geometric mean (GM), arithmetic mean (AM) and pseudo geometric mean (GM of stool samples instead of replicates). In addition, the effects of calculating the infection intensity for each age group using either AMs or GMs are compared. Differences occur in the shape of the age-infection profiles obtained by using either the arithmetic or geometric group mean. When using the AM, peak infection intensity occurs in a younger age group compared to using the GM, and all three methods of calculating individual infection intensity give the first peak of infection in the same age group. However, differences occur in the position of the second peak which occurs earlier with the two GMs than with the AM. Bootstrapping procedures show that the individual AM, gives a different age group for the first peak of infection at least 25% of the time when compared to either of the GMs, and 31% of the time for the second peak, while the two GMs give the same peak age groups around 90-92% of the time for both peaks. When using the GM, to calculate infection intensity for each age group, there are no differences between the three methods used to calculate individual infection intensity. This is confirmed by bootstrapping procedures. The results are discussed in relation to the distribution of parasites and levels of parasite aggregation. The implications of the results for field studies are also discussed.

Complex mutations in a high proportion of microsatellite loci from the protozoan parasite Plasmodium falciparum.

Microsatellite loci are generally assumed to evolve via a stepwise mutational process and a battery of statistical techniques has been developed in recent years based on this or related mutation models. It is therefore important to investigate the appropriateness of these models in a wide variety of taxa. We used two approaches to examine mutation patterns in the malaria parasite Plasmodium falciparum: (i) we examined sequence variation at 12 tri-nucleotide repeat loci; and (ii) we analysed patterns of repeat structure and heterozygosity at 114 loci using data from 12 laboratory parasite lines. The sequencing study revealed complex patterns of mutation in five of the 12 loci studied. Alleles at two loci contain indels of 24 bp and 57 bp in flanking regions, while in the other three loci, blocks of imperfect microsatellites appear to be duplicated or inserted; these loci essentially consist of minisatellite repeats, with each repeat unit containing four to eight microsatellites. The survey of heterozygosity revealed a positive relationship between repeat number and microsatellite variability for both di- and trinucleotides, indicating a higher mutation rate in loci with longer repeat arrays. Comparisons of levels of variation in different repeat types indicate that the mutation rate of dinucleotide-bearing loci is 1.6-2.1 times faster than trinucleotides, consistent with the lower mean number of repeats in trinucleotide-bearing loci. However, despite the evidence that microsatellite arrays themselves are evolving in a manner consistent with stepwise mutation model in P. falciparum, the high frequency of complex mutations precludes the use of analytical tools based on this mutation model for many microsatellite-bearing loci in this protozoan. The results call into question the generality of models based on stepwise mutation for analysing microsatellite data, but also demonstrate the ease with which loci that violate model assumptions can be detected using minimal sequencing effort.

Oesophageal atresia, related malformations, and medical problems: a family study.

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF.