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BackgroundInhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women.MethodsWe investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis.FindingsThere were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs.InterpretationStatins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Introduction/Purpose: Minimally invasive dorsal cheilectomy (MIDC) has become a popular alternative to an open approach for treating Hallux Rigidus, although the current literature is divided on its effectiveness regarding complications and patient reported outcomes. To combat a portion of the complications related to the MIDC approach, a first metatarsophalangeal (MTP) joint arthroscopy can often be added to the procedure. The combined procedure has been demonstrated to be effective at improving patient reported outcomes without increasing the complication rate relative to an open procedure. This study looks to examine the effectiveness of the MIDC with first MTP arthroscopy procedure in patients with hallux rigidus with minimum 1 year follow up. Methods: This was a multicenter retrospective review was conducted for adult patients treated with MIDC and first MTP arthroscopy between 3/1/2020 and 8/1/2022, with at least one year of postoperative follow-up data. Patient charts were reviewed for demographic information, operative time, pre and postoperative first MTP range of motion (ROM), visual analog scale (VAS), Manchester-Oxford Foot Questionnaire (MOXFQ), and EQ5DLD scores. Continuous data was expressed as a mean and standard deviation, categorical data was expressed as a percentage. Wilcoxon Rank Sum test was used to compare continuous variables. All P < 0.05 was considered significant. Results: A total of 31 patients were included in the study with an average follow-up time of 16.5 months (range: 12 to 26.2). There was 1 (3.2%) complication of an underservice EHL tendon tear, 2 (6.5%) patients were converted to a MTP fusion, and 1 (3.2%) patient underwent revision cheilectomy and capsular release for MTP joint contracture. There was a significant improvement in patient’s ROM in dorsiflexion (50 vs 89.6 degrees, P=0.002), but not in plantarflexion (11.3 vs 18.6 degrees, P=0.07). There was a significant improvement in patient’s postoperative VAS pain scores (6.4 vs 2.1, P< 0.001), MOXFQ pain scores (58.1 vs 30.7, P=0.001), MOXFQ Walking/Standing scores (56.6 vs 20.6, P=0.001), MOXFQ Social Interaction scores (47.3 vs 19.36, P=0.002), and MOXFQ Index scores (54.7 vs 22.4, P< 0.001). Conclusion: We found that MIDC with first MTP arthroscopy was effective at improving patient reported outcomes, specifically patient’s pain scores, at one year with low complication and revision rates. These results demonstrate MIDC and first MTP arthroscopy’s is an effective treatment for early-stage hallux rigidus and may be considered as an alternative to an open approach.

Introduction/Purpose: Many patients use the internet as a source for medical information regarding their medical condition. However, the accuracy and reliability of the information is variable. The recent release of general population facing artificial intelligence (AI) chatbot programs has created a potential alternative medical information source for patients. Our study examined the accuracy of the information provided by ChatGPT for total ankle arthroplasty (TAA), as determined by four fellowship-trained foot and ankle orthopedic surgeons. Methods: GPT-4, the latest ChatGPT model, was asked the 12 of the most common questions patients have regarding TAA. Its responses were recorded and evaluated by four fellowship-trained foot and ankle orthopedic surgeons on a scale of 1 – 4, with 1 representing an excellent response not requiring clarification and 4 representing an unsatisfactory response requiring significant clarification. Averages of scores for each question were recorded and an average of every score was used to develop an overall accuracy score. Results: The overall accuracy score of GPT-4 was 1.35. The responses by GPT-4 received a score of 1 for 32 of 48 (66.7%) responses. There was found to be no significant difference in scores for any of GPT-4’s responses. Conclusion: Our study found that GPT-4 performed well in providing accurate and near complete information to commonly questions asked to physicians by patients regarding TAA. Our results suggest that AI models, like GPT-4, may be an effective alternative source of medical information for patients. Further study with subsequent AI models and direct patient interaction may shed further light on the utility of this potential patient education modality. ChatGPT Response Accuracy Score Accuracy scores for ChatGPT, as determined by four foot and ankle fellowship-trained orthopedic surgeons

Introduction/Purpose: The modified Lapidus procedure (MLP) or a minimally invasive surgery distal transverse osteotomy (MISDTO) are acceptable surgical treatment options for hallux valgus. The current literature is evolving when comparing the effects of each procedure on patient reported outcomes and post-operative complications. The purpose of this study is to compare postoperative outcomes, time to weight bear, and patient reported outcomes using the Patient Reported Outcome Instrumentation System (PROMIS) for the MLP and MISDTO. Methods: This study retrospectively reviewed patients who underwent a MLP or MISDTO for hallux valgus correction at Prisma Health Midlands between February 2020 – February 2022. Data collected included: demographic data, postoperative outcomes, time to weight bear, and PROMIS scores, including Pain Interference (PI), Physical Function (PF), and Mobility scores. Paired Student’s T-Test and Wilcoxon Rank Sum test were used to compare continuous variables and Chi-Squared test for categorical variables. Results: A total of 81 patients undergoing MLP and 78 undergoing MISDTO were included in the study. Average follow-up for MLP and MISDTO patients was 53.7 and 43.4 weeks, respectively. MLP demonstrated significant improvement in PI (52.5 vs 56.8, P< 0.001) and Mobility (46.3 vs 43.4, P=0.044) scores, while MISDTO demonstrated a significant improvement in PI (48.8 vs 57.1, P< 0.001), PF (50.2 vs 44.9, P< 0.001), and Mobility (49 vs 42.8, P< 0.001) scores. MISDTO patients had significantly larger improvements in PI (7.6 vs 4.5, P=0.008), PF (5.3 vs 2.2, P=0.026), and Mobility (5.5 vs 2.9, P=0.02) compared to MLP patients. MISDTO patients had a significantly lower non-union rate (13.6% vs 2.6%, P=0.025), hardware failure rate (0% vs 9.9%, P=0.007), and time to weight-bear (2.2 vs 7.8 weeks, P< 0.001). Conclusion: Both MLP and MISDTO procedures are effective treatments for improving the pain and mobility issues associated with hallux valgus while maintaining patients’ function. MISDTO was found to improve patient reported outcomes significantly more than MLP, with a lower non-union rate, lower hardware failure rate, and shorter time to weight-bear. These findings suggest MISDTO is superior to MLP in improving patient reported outcomes and postoperative outcomes in the treatment of hallux valgus. Further study multicenter and long term outcome studies could be useful further evaluate these short term findings.

Background: Hindfoot fusion procedures are common for the treatment of end-stage arthritis or deformity. Surgical treatments for these conditions include talonavicular joint (single) arthrodesis, talonavicular and subtalar (double) arthrodesis, or talonavicular, subtalar, and calcaneocuboid (triple) arthrodesis. This study evaluated the complication rate, revision surgery rate, and hardware removal rate for those treated with either single, double, or triple arthrodesis. Methods: A retrospective review was conducted for patients who underwent single ( Current Procedural Terminology [ CPT ] code 28740), double ( CPT 28725 and 28740), or triple ( CPT 28715) arthrodesis to treat hindfoot arthritis/deformity ( International Classification of Diseases, Ninth Revision [ ICD-9 ] code: 734, International Classification of Diseases, Tenth Revision [ ICD-10 ] codes: M76821, M76822, and M76829) from 2005 to 2022 using the South Carolina Revenue and Fiscal Affairs databank. Data collected included demographics, comorbidities, procedure data, and postoperative outcomes within 1 year of principal surgery. Student t test, chi-squared test, and multivariable logistic regression analysis were utilized during data analysis. Results: A total of 433 patients were identified, with 248 undergoing single arthrodesis, 67 undergoing double arthrodesis, and 118 undergoing triple arthrodesis. There was no significant difference between single, double, and triple arthrodesis in the rate of complications, hardware removals, revision surgeries, or 30-day readmission when controlling for confounding variables. However, a decrease in Charlson Comorbidity Index (CCI) was found to be predictive of an increase in the revision surgery rate (OR = 0.46, 95% CI 0.22-0.85, P = .02). Conclusion: We found no difference in the rate of complications, hardware removals, or revision surgeries in those undergoing single, double, or triple arthrodesis. Surprisingly we found that a lower Charlson Comorbidity Index, indicating a healthier patient had a significant relationship with a higher rate of revision surgery. Further study including radiographic indications for surgery or the impact of overall health status on revision surgery rates may further elucidate the other components of this relationship. Level of Evidence: Level III, cohort study.

Background:. Artificial intelligence (AI) holds potential in improving medical education and healthcare delivery. ChatGPT is a state-of-the-art natural language processing AI model which has shown impressive capabilities, scoring in the top percentiles on numerous standardized examinations, including the Uniform Bar Exam and Scholastic Aptitude Test. The goal of this study was to evaluate ChatGPT performance on the Orthopaedic In-Training Examination (OITE), an assessment of medical knowledge for orthopedic residents. Methods:. OITE 2020, 2021, and 2022 questions without images were inputted into ChatGPT version 3.5 and version 4 (GPT-4) with zero prompting. The performance of ChatGPT was evaluated as a percentage of correct responses and compared with the national average of orthopedic surgery residents at each postgraduate year (PGY) level. ChatGPT was asked to provide a source for its answer, which was categorized as being a journal article, book, or website, and if the source could be verified. Impact factor for the journal cited was also recorded. Results:. ChatGPT answered 196 of 360 answers correctly (54.3%), corresponding to a PGY-1 level. ChatGPT cited a verifiable source in 47.2% of questions, with an average median journal impact factor of 5.4. GPT-4 answered 265 of 360 questions correctly (73.6%), corresponding to the average performance of a PGY-5 and exceeding the corresponding passing score for the American Board of Orthopaedic Surgery Part I Examination of 67%. GPT-4 cited a verifiable source in 87.9% of questions, with an average median journal impact factor of 5.2. Conclusions:. ChatGPT performed above the average PGY-1 level and GPT-4 performed better than the average PGY-5 level, showing major improvement. Further investigation is needed to determine how successive versions of ChatGPT would perform and how to optimize this technology to improve medical education. Clinical Relevance:. AI has the potential to aid in medical education and healthcare delivery.

Meaning-making is an important component in the psychological recovery from collective traumas. However, not enough is known about what individual differences might facilitate meaning-oriented approaches to coping and recovering from traumas. We predicted that free will beliefs, which afford people the perception of volitional autonomy over their actions, would be an important antecedent to sense-making and meaning-focused coping. We tested this conceptual hypothesis in the context of two distinct collective traumas. In Study 1 (n = 342), the comprehension facet of meaning in life (which is the facet most related to sense-making) mediated the relationship between free will beliefs and lower psychological distress related to the COVID-19 global pandemic. In Study 2 (n = 571), meaning-focused coping, but not other coping styles, mediated the relationship between free will beliefs and psychological recovery (i.e., lower distress over time) in a longitudinal sample collected in the aftermath of Hurricane Harvey. We interpreted our findings as robust support for our hypothesis, the strength of which is bolstered by the distinct settings and methodologies with which the data were collected. We conclude by discussing our results in relation to the view that free will beliefs afford a more agentic approach to meaning-making, which ultimately facilities more effective psychological recovery from collective trauma.

There has been little innovation in identifying novel insulin sensitizers. Metformin, developed in the 1920s, is still used first for most Type 2 diabetes patients. Mice with genetic reduction of p52Shc protein have improved insulin sensitivity and glucose tolerance. By high-throughput screening, idebenone was isolated as the first small molecule 'Shc Blocker'. Idebenone blocks p52Shc's access to Insulin Receptor to increase insulin sensitivity. In this work the avidity of 34 novel idebenone analogs and 3 metabolites to bind p52Shc, and to block the interaction of p52Shc with the Insulin receptor was tested. Our hypothesis was that if an idebenone analog bound and blocked p52Shc's access to insulin receptor better than idebenone, it should be a more effective insulin sensitizing agent than idebenone itself. Of 34 analogs tested, only 2 both bound p52Shc more tightly and/or blocked the p52Shc-Insulin Receptor interaction more effectively than idebenone. Of those 2 only idebenone analog #11 was a superior insulin sensitizer to idebenone. Also, the long-lasting insulin-sensitizing potency of idebenone in rodents over many hours had been puzzling, as the parent molecule degrades to metabolites within 1 h. We observed that two of the idebenone’s three metabolites are insulin sensitizing almost as potently as idebenone itself, explaining the persistent insulin sensitization of this rapidly metabolized molecule. These results help to identify key SAR = structure-activity relationship requirements for more potent small molecule Shc inhibitors as Shc-targeted insulin sensitizers for type 2 diabetes.

Considerable evidence suggests that modifiable risk factors for adverse pregnancy outcomes such as preterm birth and low birthweight include obesity, sedentary behavior, and infections. There is a growing consensus that the preconceptional and interconceptional periods may be an ideal time for preventive intervention targeting these risk factors; enhancing health before pregnancy would subsequently reduce the risk for poor pregnancy outcomes. This paper provides an overview of the development of a health behavior intervention, Strong Healthy Women, that aims to improve women's preconceptional and interconceptional health. We describe the rationale, delivery, and targeted outcomes of the program, as well as the design of an ongoing trial currently testing program efficacy. The content areas are also discussed and include pregnancy-conception, stress, physical activity, nutrition, infection, sources of smoke in the home, and substance use. This intervention protocol may offer researchers and healthcare professionals a framework for designing other programs aiming to improve women's preconceptional health. [ABSTRACT FROM AUTHOR]

Objective: To improve understanding of women's use of health care before pregnancy, by analyzing how the health status and health risks of pre- and interconceptional women are associated with health services use.Data Source: Data are from a cross-sectional random-digit dial telephone survey of a representative sample of 2002 women ages 18-45 years from the Central Pennsylvania Women's Health Study (CePAWHS). A subsample of 1,325 respondents with current reproductive capacity, classified by reproductive life stage (preconceptional or interconceptional), was analyzed.Study Design: Bivariate and multiple logistic regression analyses were conducted to determine how health needs (including indices of health status and health risks related to adverse pregnancy outcomes) are associated with five indicators of health services use (receipt of a regular physical exam, obstetrician-gynecologist [ob/gyn] visit, receipt of a set of recommended screening services, receipt of health counseling services on general health topics, and receipt of pregnancy-related counseling), controlling for predisposing and enabling variables.Principal Findings: Only half of women at risk of pregnancy report receiving counseling about pregnancy planning in the past year. One-third of women surveyed did not receive routine physical examinations and screening services, and over half received little or no health counseling. Multivariate analyses showed that all the measures of health needs except for negative health behavior were related to some type of health services use. Psychosocial stress was associated with having a recent ob/gyn visit, with receiving general health counseling, and with receiving pregnancy planning counseling. Cardiovascular risk was positively associated with receiving general health counseling and a regular physical exam, but negatively associated with seeing an ob/gyn. Positive health behaviors were associated with receiving screening services and with receiving general health counseling. Preconceptional reproductive life stage was positively associated with receiving a regular physical exam and negatively associated with having an ob/gyn visit.Conclusions: Pre- and interconceptional women with specific health care needs may not receive appropriate health care before pregnancy. Improving pregnancy experiences and outcomes requires more comprehensive preconception health care and more preventive care before the first pregnancy. [ABSTRACT FROM AUTHOR]

Background: Many consensus guidelines recommend routine surveillance to detect recurrent disease among cancer survivors. We compare surveillance care receipt to guideline recommendations.Methods: Cohorts of patients aged 30 years or older diagnosed with breast, colorectal, endometrial, lung, or prostate cancer between 1990 and 1995 and treated with curative intent were identified (n = 100 per site). Receipt and indications for examinations and procedures were abstracted from medical records for as long as 5 years after treatment. Kaplan-Meier product estimates were used to estimate time to initial and subsequent service receipt.Results: Most cancer patients received the recommended minimum number of physical examinations after treatment. In fact, a sizable number of cancer survivors received physical examinations at a frequency in excess of what is currently recommended. Similarly, most of these cancer survivors received recommended testing for local recurrence. Yet, less than two thirds of colorectal cancer patients received recommended colon examinations in the initial year after treatment. Among colorectal, lung, and prostate cancer patients who received recommended initial local recurrence testing, repeat testing tended to occur more frequently than what is currently recommended. The use of testing for metastatic disease that is not recommended in guidelines is also commonplace among these cancer survivors.Conclusions: Among cohorts of cancer patients, we found wide variation in the use of surveillance care, including patterns of care receipt reflective of both underuse and overuse relative to guideline recommendations. Clinical reasons for these variations and the cost and health implications deserve further study. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates. Methods Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation. Results We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation. Conclusions Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood.

This study used population-based data to examine how health status and risks vary by reproductive life stage, with particular focus on the proximal risks for preterm birth and low birthweight (LBW) infants in preconceptional and interconceptional women. Data are from the Central Pennsylvania Women's Health Study (CePAWHS), which included a telephone survey of a representative sample of 2,002 women ages 18-45 years residing in largely rural central Pennsylvania. Women were classified according to reproductive stage--preconceptional, interconceptional, and postconceptional--on the basis of pregnancy history and reproductive capacity. Multiple indicators of health status and health risks were examined by reproductive stage, stratified by age group (ages 18-34 and ages 35-45). Results show that many risk factors varied significantly by reproductive stage and by age group within reproductive stage. Preconceptional and interconceptional women exhibited several unhealthy behaviors (e.g., binge drinking, nutritional deficits, physical inactivity). Younger pre- and interconceptional women (ages 18-34) had more gynecologic infections, some less favorable health behaviors, and more psychosocial stress than older women (ages 35-45) in the same reproductive stages. Older preconceptional women were more likely to have chronic conditions (hypertension, high cholesterol) than younger preconceptional women. Results suggest how interventions could be tailored to women's reproductive stages. [ABSTRACT FROM AUTHOR]

This paper describes a proactive product stewardship program for glass fibers. That effort included epidemiological studies of workers, establishment of stringent workplace exposure limits, liaison with customers on safe use of products and, most importantly, a research program to evaluate the safety of existing glass fiber products and guide development of new even safer products. Chronic inhalation exposure bioassays were conducted with rodents and hamsters. Amosite and crocidolite asbestos produced respiratory tract cancers as did exposure to "biopersistent" synthetic vitreous fibers. "less biopersistent" glass fibers did not cause respiratory tract cancers. Corollary studies demonstrated the role of slow fiber dissolution rates and biopersistence in cancer induction. These results guided development of safer glass fiber products and have been used in Europe to regulate fibers and by IARC and NTP in classifying fibers. IARC concluded special purpose fibers and refractory ceramic fibers are "possibly carcinogenic to humans" and insulation glass wool, continuous glass filament, rock wool and slag wool are "not classifiable as to their carcinogenicity to human." The NTP's 12th report on carcinogens lists "Certain Glass Wool Fibers (Inhalable)" as "reasonably anticipated to be a human carcinogen." "Certain" in the descriptor refers to "biopersistent" glass fibers and excludes "less biopersistent" glass fibers., (Copyright © 2012 Elsevier Inc. All rights reserved.)

One Healthy People 2010 objective is that 80% of women in the United States start a pregnancy with optimal levels of folic acid. This often requires women to use folic acid supplements preconceptionally to get adequate levels. Efforts to achieve the objective have resulted in a suboptimal floor effect at less than 50% of women. We advance a framework based on exemplification theory, identifying supplementation as an additive action in which two role models exemplify folic acid supplementation among women of reproductive age able to become pregnant (n = 1,258). The women were participants in Phase I of the Central Pennsylvania Women's Health Study (CePAWHS). One exemplar identified represents the positive habits aligned with supplementers considering a pregnancy sometime in their future, while the other resides in the exemplification of positive habits aligned with supplementers not considering a pregnancy sometime in their future but still able to become pregnant. Among women not considering a future pregnancy, daily green salad consumption, weekly fish consumption, having had a health care visit in the past year, and having had any ob/gyn visit in the past 2 years resulted in increased odds of folic acid supplement use in a multivariable model. In the same model, an increase in age resulted in increased odds of folic acid supplement use. Among women considering a future pregnancy, not smoking cigarettes, having higher levels of psychosocial stress, and having higher levels of interaction social support resulted in increased odds of folic acid supplement use in a multivariable model. In the same model, those who have had a health care visit in the past year, as well as those who have received pregnancy planning counseling, were also more likely to use a folic acid supplement. Implications for strategic communication are considered.

Objectives: We sought to examine variables associated with mental health among rural women of reproductive age, with particular attention given to rural area type and farm residence., Methods: We analyzed data from the Central Pennsylvania Women's Health Study, which included a random-digit-dialed survey of women aged 18 to 45 years. Hierarchical multiple linear and logistic regression models were estimated to predict 3 mental health outcomes: score on a mental health measure, depressive symptoms, and diagnosed depression or anxiety., Results: Mental health outcomes were associated with different factors. Farm residence was associated with higher mental health score, and the most isolated rural residence was associated with less diagnosed depression or anxiety. Elevated psychosocial stress was consistently significant across all models. A key stress modifier, self-esteem, was also consistently significant across models. Other variables associated with 2 of the outcomes were intimate partner violence exposure and affectionate social support., Conclusions: Farm residence may be protective of general mental health for women of reproductive age, and residence in isolated rural areas may decrease access to mental health screening and treatment, resulting in fewer diagnoses of depression or anxiety.

Objective: Engaging women in preconception prevention may be challenging if at-risk women do not perceive increased risk. This study examined predictors of perceiving increased risk for preterm/low birthweight birth., Study Design: Using the Central Pennsylvania Women's Health Study, a population-based sample of reproductive-age women, we analyzed whether sociodemographics, health and pregnancy history, health behaviors, attitudes, or health care utilization predicted risk perception of preterm/low-birthweight birth., Results: Of the 645 women analyzed, 157 (24%) estimated their risk of preterm/low-birthweight birth to be very or somewhat likely. Higher perceived risk was associated with being underweight, previous preterm/low-birthweight birth, having a mother with previous preterm/low-birthweight birth, lower perceived severity of preterm/low birthweight, and smoking., Conclusions: Several factors known to predict preterm/low birthweight did influence risk perception in this study, whereas others did not. Further research on how these factors have an impact on participation in preconception care programs is warranted.

Context: Preterm birth and low birthweight remain high priority public health problems and are associated with increased risk of infant mortality as well as long-term health impairments. Although 20% of all births nationally are to rural women, relatively little attention has been paid to pregnancy outcomes in rural areas relative to more urbanized areas., Purpose: This study examines the relationship of individual- and community-level socioeconomic, health care, and health status-related characteristics to preterm birth and low birthweight outcomes among women living in urban and various types of rural communities., Methods: Vital record data on singleton first births to residents of a 28-county region in central Pennsylvania in 2002 (N = 11,546) were merged with zip code-level information from the census and residence in a primary care health professional shortage area. Rural-urban commuting area codes were also appended. Multiple logistic regression analyses were performed to model risks of preterm birth and low birthweight using generalized estimating equations to account for clustering within zip code., Findings: Women residing in large rural city-focused areas had lower adjusted odds of both preterm birth and low birthweight as compared to urban women, controlling for individual risk factors including maternal demographic characteristics, health conditions, and prenatal care use. In contrast, risks of these adverse birth outcomes were not significantly lower among women living in more rural areas relative to those in urban communities., Conclusions: Reduced risks of preterm birth and low birthweight risk are associated with some, but not all types of rural as compared to urban communities.

One limitation of the existing tagging SNP selection algorithms is that they assume the reported genotypes are error free. However, genotyping errors are often unavoidable in practice. Many tagging SNP selection methods depend heavily on the estimated haplotype frequencies. Recent studies have demonstrated that even slight genotyping errors can lead to serious consequences with regard to haplotype reconstruction and frequency estimation. Here we present a tagging SNP selection method that allows for genotyping errors. Our method is a modification of the pair-wise r(2) tagging SNP selection algorithm proposed by Carlson et al. (2004). We have replaced the standard EM algorithm in Carlson's method with an EM that accounts for genotyping errors, in an attempt to obtain better estimates of the haplotype frequencies and r(2) measure. Through simulation studies we compared the performance of our modified algorithm with that of the original algorithm. We found that the number of tags selected by both methods increased with increasing genotyping errors, though our method led to smaller increase. The power of haplotype association tests using the selected tags decreased dramatically with increasing genotyping errors. The power of single marker tests also decreased, but the reduction was not as much as the reduction in power of haplotype tests. When restricting the mean number of tags selected by both methods to be similar to the baseline number, Carlson's method and our method led to similar power for the subsequent haplotype and single marker tests. Our results showed that, by accounting for random genotyping errors, our method can select tagging SNPs more efficiently than Carlson's method. The computer program that implements our modified tagging SNP selection algorithm is available at our web site: http://www.personal.psu.edu/tuy104/.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in approximately 10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Objectives: We determined risks of short-term (2-year) hip fracture in a nationally representative, prospective cohort of community-dwelling elderly people 70 years or older., Methods: We used self-report data from 2 waves of the Asset and Health Dynamics Survey (n = 5630). Sample-weighted logistic regression analyses were conducted to determine risk of hip fracture in relation to several demographic, cognitive, physical, and socioeconomic indicators., Results: During the 2-year study period, 102 participants reported a new hip fracture. Several indicators of physical functioning and cognitive status, including incorrect delayed word recall and inability to lift 10 lbs (4.5 kg), were significantly associated with hip fracture risk. In the final model, mobile home residents, individuals without Medicare part B insurance, and those without a high-school diploma were at more than a 2-fold risk of hip fracture. Educational level, physical functioning, and insurance status were the top 3 contributors to hip fracture risk., Conclusions: In addition to functional status measures, health insurance status, educational level, and type of residence appear to be independent predictors of hip fracture.

Because of the multiple biochemical pathways that require iron, iron deficiency can impact brain metabolism in many ways. The goal of this study was to identify a molecular footprint associated with ongoing versus long term consequences of iron deficiency using microarray analysis. Rats were born to iron-deficient mothers, and were analyzed at two different ages: 21 days, while weaning and iron-deficient; and six months, after a five month iron-sufficient recovery period. Overall, the data indicate that ongoing iron deficiency impacts multiple pathways, whereas the long term consequences of iron deficiency on gene expression are more limited. These data suggest that the gene array profiles obtained at postnatal day 21 reflect a brain under development in a metabolically compromised setting that given appropriate intervention is mostly correctable. There are, however, long term consequences to the developmental iron deficiency that could underlie the neurological deficits reported for iron deficiency.

Objective: Single nucleotide polymorphisms (SNPs) serve as effective markers for localizing disease susceptibility genes, but current genotyping technologies are inadequate for genotyping all available SNP markers in a typical linkage/association study. Much attention has recently been paid to methods for selecting the minimal informative subset of SNPs in identifying haplotypes, but there has been little investigation of the effect of missing or erroneous genotypes on the performance of these SNP selection algorithms and subsequent association tests using the selected tagging SNPs. The purpose of this study is to explore the effect of missing genotype or genotyping error on tagging SNP selection and subsequent single marker and haplotype association tests using the selected tagging SNPs., Methods: Through two sets of simulations, we evaluated the performance of three tagging SNP selection programs in the presence of missing or erroneous genotypes: Clayton's diversity based program htstep, Carlson's linkage disequilibrium (LD) based program ldSelect, and Stram's coefficient of determination based program tagsnp.exe., Results: When randomly selected known loci were relabeled as 'missing', we found that the average number of tagging SNPs selected by all three algorithms changed very little and the power of subsequent single marker and haplotype association tests using the selected tagging SNPs remained close to the power of these tests in the absence of missing genotype. When random genotyping errors were introduced, we found that the average number of tagging SNPs selected by all three algorithms increased. In data sets simulated according to the haplotype frequecies in the CYP19 region, Stram's program had larger increase than Carlson's and Clayton's programs. In data sets simulated under the coalescent model, Carlson's program had the largest increase and Clayton's program had the smallest increase. In both sets of simulations, with the presence of genotyping errors, the power of the haplotype tests from all three programs decreased quickly, but there was not much reduction in power of the single marker tests., Conclusions: Missing genotypes do not seem to have much impact on tagging SNP selection and subsequent single marker and haplotype association tests. In contrast, genotyping errors could have severe impact on tagging SNP selection and haplotype tests, but not on single marker tests.

Although permutation testing has been the gold standard for assessing significance levels in studies using multiple markers, it is time-consuming. A Bonferroni correction to the nominal p-value that uses the underlying pair-wise linkage disequilibrium (LD) structure among the markers to determine the number of effectively independent tests has recently been proposed. We propose using the number of independent LD blocks plus the number of independent single-nucleotide polymorphisms for correction. Using the Collaborative Study on the Genetics of Alcoholism LD data for chromosome 21, we simulated 1,000 replicates of parent-child trio data under the null hypothesis with two levels of LD: moderate and high. Assuming haplotype blocks were independent, we calculated the number of independent statistical tests using 3 haplotype blocking algorithms. We then compared the type I error rates using a principal components-based method, the three blocking methods, a traditional Bonferroni correction, and the unadjusted p-values obtained from FBAT. Under high LD conditions, the PC method and one of the blocking methods were slightly conservative, whereas the 2 other blocking methods exceeded the target type I error rate. Under conditions of moderate LD, we show that the blocking algorithm corrections are closest to the desired type I error, although still slightly conservative, with the principal components-based method being almost as conservative as the traditional Bonferroni correction.

We consider 12 event-related potentials and one electroencephalogram measure as disease-related traits to compare alcohol-dependent individuals (cases) to unaffected individuals (controls). We use two approaches: 1) two-way analysis of variance (with sex and alcohol dependency as the factors), and 2) likelihood ratio tests comparing sex adjusted values of cases to controls assuming that within each group the trait has a 2 (or 3) component normal mixture distribution. In the second approach, we test the null hypothesis that the parameters of the mixtures are equal for the cases and controls. Based on the two-way analysis of variance, we find 1) males have significantly (p < 0.05) lower mean response values than females for 7 of these traits. 2) Alcohol-dependent cases have significantly lower mean response than controls for 3 traits. The mixture analysis of sex-adjusted values of 1 of these traits, the event-related potential obtained at the parietal midline channel (ttth4), found the appearance of a 3-component normal mixture in cases and controls. The mixtures differed in that the cases had significantly lower mean values than controls and significantly different mixing proportions in 2 of the 3 components. Implications of this study are: 1) Sex needs to be taken into account when studying risk factors for alcohol dependency to prevent finding a spurious association between alcohol dependency and the risk factor. 2) Mixture analysis indicates that for the event-related potential "ttth4", the difference observed reflects strong evidence of heterogeneity of response in both the cases and controls.

We explored the utility of selecting a genetically predisposed subgroup to increase the finding of a genetic signal in the Genetic Analysis Workshop 14 Collaborative Study on the Genetics of Alcoholism dataset. A subgroup of affected probands with low environmental risk exposures was defined using a susceptibility score calculated from an environmental risk model. Thirty-nine probands with highly positive scores were selected, along with their parents, for use in a genotypic transmission disequilibrium test (TDT) test. We compared the results of the genotypic TDT in this subgroup to the TDT results using all probands and their parents. For some markers, the susceptibility scoring approach resulted in smaller p-values, while for other markers, evidence for a genetic signal weakened. Further explorations into genetic and environmental population characteristics that benefit from this approach are warranted.

Individual variation in genetic, phenotypic and environmental factors could lead to significant differences in rates of drug metabolism, in clinical responses to drugs, and in drug side effects. The impact of population heterogeneity on treatment effect estimation and on assessment and application of clinical trial findings has been less than fully studied. In this paper, we studied the properties of models that reflect population heterogeneity of clinical trial samples by unmeasured covariates such as genetic susceptibility. The impact of heterogeneity on the estimation of treatment effect in a two-armed placebo or active-controlled clinical trial was quantified using logistic regression models. We also proposed a two-stage clinical trial, where the effects of individual drug-response-related covariates were estimated in a 'training data set' in the first stage of the trial. In the second stage of the trial, a subgroup of individuals with enhanced (or reduced) sensitivity to drug treatments in a heterogeneous risk cohort was identified based on information about their drug-related characteristics. Only these 'responders' were included in the subsequent efficacy test. Our simulation results showed that population heterogeneity could lead to biased estimation of treatment effect not only in the contaminated groups but also in the uncontaminated groups. A two-stage trial could greatly increase the power of an efficacy test over a 'full trial' even with fewer individuals enrolled in the trial; results would apply to a more highly specified population. The bigger the covariate effects, the more efficient the two-stage trial is compared to a 'full trial'., (Copyright 2005 John Wiley & Sons, Ltd.)

Purpose: Women with chronic medical conditions are at increased risk for adverse pregnancy outcomes, yet contraceptive use by these women has not been well described. The purpose of this study was to describe contraceptive use by diabetic and overweight/obese women compared with women without these conditions., Methods: Using cross-sectional data from the 11 states participating in the optional Family Planning Module of the Behavioral Risk Factor Surveillance System in 2000, we analyzed contraceptive use among 7,943 sexually active women of reproductive age (18-44) who were not trying to conceive. Using logistic regression techniques, we modeled the effect of diabetes and overweight/obesity on contraceptive nonuse, controlling for age, race/ethnicity, marital status, education, income, and health insurance coverage., Main Findings: Contraceptive nonuse was reported by 1,500 (18.9%) of the total sample, 31 (25.8%) diabetic women, 371 (20.0%) overweight women, and 385 (23.4%) obese women. In the multivariable model, obesity was significantly associated with contraceptive nonuse (adjusted odds ratio [OR] 1.34, 95% confidence interval [CI] 1.16-1.55), but there were no significant differences in contraceptive nonuse for diabetic women (adjusted OR 1.23, 95% CI 0.80-1.87) or overweight women (adjusted OR 1.14, 95% CI 0.99-1.31). Older, Black, Hispanic, married, less educated, and women without health insurance were more likely to report contraceptive nonuse., Conclusion: Among women with need for contraception, obese women were more likely to report contraceptive nonuse than normal weight women. Because women with chronic conditions like obesity are at higher risk of pregnancy-related complications and adverse pregnancy outcomes, proper contraceptive use and unintended pregnancy avoidance is a priority.

Background: Many consensus guidelines recommend routine surveillance to detect recurrent disease among cancer survivors. We compare surveillance care receipt to guideline recommendations., Methods: Cohorts of patients aged 30 years or older diagnosed with breast, colorectal, endometrial, lung, or prostate cancer between 1990 and 1995 and treated with curative intent were identified (n = 100 per site). Receipt and indications for examinations and procedures were abstracted from medical records for as long as 5 years after treatment. Kaplan-Meier product estimates were used to estimate time to initial and subsequent service receipt., Results: Most cancer patients received the recommended minimum number of physical examinations after treatment. In fact, a sizable number of cancer survivors received physical examinations at a frequency in excess of what is currently recommended. Similarly, most of these cancer survivors received recommended testing for local recurrence. Yet, less than two thirds of colorectal cancer patients received recommended colon examinations in the initial year after treatment. Among colorectal, lung, and prostate cancer patients who received recommended initial local recurrence testing, repeat testing tended to occur more frequently than what is currently recommended. The use of testing for metastatic disease that is not recommended in guidelines is also commonplace among these cancer survivors., Conclusions: Among cohorts of cancer patients, we found wide variation in the use of surveillance care, including patterns of care receipt reflective of both underuse and overuse relative to guideline recommendations. Clinical reasons for these variations and the cost and health implications deserve further study.

Given the growing importance of molecular profiling of breast cancer, we initiated a small study to test whether human breast biopsies obtained via cryopreservation large core needle biopsy (C-LCNB) provided similar gene expression profiles compared with 'optimally handled' standard large core needle biopsy (S-LCNB) specimens. Five matched pairs of C-LCNB versus S-LCNB were obtained at the same visit, and subjected to gene array expression analysis using the Affymetrix system with U133A chips. No significant changes in gene expression were identified comparing the C-LCNB versus the matched S-LCNB from individual patients. This was corroborated by a paired t-test analysis, which supported the hypothesis that the S/C biopsies measured equivalent samples. A small number of genes (17) showed decreased expression when second biopsies were compared with first biopsies, suggesting a slight patient response to the first biopsy. A scatter plot analysis comparing first biopsy versus second biopsy values disclosed a slope of 0.859, further indicating that the first biopsy affects the second biopsy measurement. It therefore appears that conventional biopsies, when handled appropriately, provide RNA which is equivalent to RNA from biopsies which are frozen immediately, but that multiple biopsy protocols may introduce additional complexities.

Comorbidity of depression and smoking is well recognized, but results from studies that have assessed alternative explanations have varied by the level of smoking and the study method. We examined all 13 etiology models of comorbidity described by Neale and Kendler (American Journal of Genetics, 57, 935-953, 1995) for depression and each of four levels of smoking to shed light on the role that differing definitions might have played in generating the conflicting findings. Data came from 979 young adults aged 26-35 years who participated in an epidemiological cohort study in southeastern Michigan. Respondent and family history data on parental smoking and depression were analyzed using the biometric modeling method for family data, which Rhee and colleagues (Journal of Child Psychology and Psychiatry and Allied Disciplines, 44, 612-636, 2003; Behavior Genetics, 34, 251-265, 2004) have shown to be valid more frequently than traditional prevalence analyses. Results of the biometric model fitting suggested that for ever smoking, the comorbidity with depression may be related to chance or a high liability threshold for smoking only. In contrast, a correlated liabilities model fit the data best for the comorbidity of depression with daily, heavy, and nicotine-dependent smoking. The familial correlations accounted for 73%-95% of the total variance shared between depression and these levels of smoking. These results differ from analyses of these data using a traditional prevalence approach, which found no evidence of shared familial liability. The conflicting findings of the studies that have examined the relationship between smoking and depression may be attributable to differences in definition of the disorders and the methods used to analyze them.

Background: Genome scans for hypertension have yielded inconsistent results. The non-replication of significant or suggestive linkage might be due to lack of power of individual studies. Here, we conducted a genome scan meta-analysis for hypertension in an attempt to increase statistical power and to enhance evidence of linkage., Methods: A newly developed Genome Search Meta-analysis (GSMA) method was applied to pool the results obtained from six scans reported in five papers., Results: Our analysis did not find any regions with genome-wide significant linkage to hypertension. We did identify several regions with suggestive linkage, including 2p, 5q, 6q, 8p, 9p, 9q, and 11q., Conclusions: It seems that no region has a uniformly large impact on hypertension and that susceptibility genes for hypertension may be very difficult to detect.

Loss of heterozygosity (LOH) in chromosomal regions that harbor tumor suppressor genes from tumor tissue may lead to decreased survival time in cancer patients with squamous cell carcinoma of the head and neck (HNSCC). We studied 8 regions frequently lost in HNSCC in 150 patients having a primary diagnosis of HNSCC. Tumor and normal tissue DNA were genotyped for microsatellite repeat markers in 8 unlinked chromosomal regions. The association between LOH and death from HNSCC was investigated, weighted by number of informative markers per region and adjusted for age at diagnosis, self-reported race, tumor stage and current smoking status. LOH at 3 chromosomal regions were independently associated with reduced survival. A greater risk for cancer mortality was observed for LOH at chromosomal regions 3p24.3-p14.3 (p = 0.02), 8p21.3-p11.21 (p = 0.02) and 9p24.2-p21.2 (p = 0.03). In these regions, LOH at one or more markers was observed in 66.9%, 43.3% and 60.6% of patients, respectively. Survival times were significantly shorter for those with LOH at marker NEFL on 8p21.2 (relative risk = 6.15; p = 0.0002) and at D9S126 on 9p21.2 (relative risk = 5.96; p = 0.0003). Our results indicate that LOH at several chromosomal sites may offer additional independent prognostic information beyond traditional indicators such as tumor stage and age., (Copyright 2004 Wiley-Liss, Inc.)

Background: Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates., Methods: Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation., Results: We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation., Conclusions: Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood.

A survey questionnaire regarding perceptions of risk and genetic susceptibility to Alzheimer's disease (AD) was completed by 518 offspring of AD cases from families with multiple affected, ascertained as part of a genetic linkage study of late onset AD. The questionnaire focused on respondents' perceptions of their own risk for AD as well as on the properties of real and hypothetical susceptibility tests, including error rates for false-positive and false-negative test results. Our findings showed that about 20% of the sample would refuse a susceptibility test with zero error rates, about 40% would accept tests with very high error rates in both directions, and the remainder would exercise some discrimination. Acceptance of high test error rates was significantly associated with male gender, low education, and high perceived lifetime risk of AD. In a previous paper related to this work, we showed that physicians caring for these families exercised much more discrimination in judging the acceptability of genetic tests they would offer to these same respondents. The findings show that there is a pressing need to educate the public, particularly those with relatives affected by a complex disease, to expect standards of accuracy for genetic tests comparable to those that prevail in other diagnostic and prognostic testing efforts in the broad field of clinical medicine.

Background: Gene x environment models are widely used to assess genetic and environmental risks and their association with a phenotype of interest for many complex diseases. Mixed generalized linear models were used to assess gene x environment interactions with respect to systolic blood pressure on sibships adjusting for repeated measures and hierarchical nesting structures. A data set containing 410 sibships from the Framingham Heart Study offspring cohort (part of the Genetic Analysis Workshop 13 data) was used for all analyses. Three mixed gene x environment models, all adjusting for repeated measurement and varying levels of nesting, were compared for precision of estimates: 1) all sibships with adjustment for two levels of nesting (sibs within sibships and sibs within pedigrees), 2) all sibships with adjustment for one level of nesting (sibs within sibships), and 3) 100 data sets containing random draws of one sibship per extended pedigree adjusting for one level of nesting., Results: The main effects were: gender, baseline age, body mass index (BMI), hypertensive treatment, cigarettes per day, grams of alcohol per day, and marker GATA48G07A. The interaction fixed effects were: baseline age by gender, baseline age by cigarettes per day, baseline age by hypertensive treatment, baseline age by BMI, hypertensive treatment by BMI, and baseline age by marker GATA48G07A. The estimates for all three nesting techniques were not widely discrepant, but precision of estimates and determination of significant effects did change with the change in adjustment for nesting., Conclusion: Our results show the importance of the adjustment for all levels of hierarchical nesting of sibs in the presence of repeated measures.