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1.  Intestinal pseudo-obstruction in patients with systemic lupus erythematosus: A real diagnostic challenge 
World Journal of Gastroenterology : WJG  2014;20(32):11443-11450.
Intestinal pseudo-obstruction secondary to systemic lupus erythematosus (SLE) is a rare syndrome described in recent decades. There are slightly over 30 published cases in the English language literature, primarily associated with renal and hematological disease activity. Its presentation and evolution are a diagnostic challenge for the clinician. We present four cases of intestinal pseudo-obstruction due to lupus in young Mexican females. One patient had a previous diagnosis of SLE and all presented with a urinary tract infection of varying degrees of severity during their evolution. We consider that recognition of the disease is of vital importance because it allows for establishing appropriate management, leading to a better prognosis and avoiding unnecessary surgery and complications.
doi:10.3748/wjg.v20.i32.11443
PMCID: PMC4145788  PMID: 25170234
Intestinal pseudo-obstruction; Systemic lupus erythematosus; Uretero-hydronephrosis; Urinary tract infection; Diagnostic challenge
2.  Drinking buddies and their prospective influence on alcohol outcomes: Alcohol expectancies as a mediator 
The process by which peers or the social network influence individual alcohol use, particularly among adults, remains a necessary area of research. The purpose of the present study was to examine the longitudinal influence of “drinking buddies” on alcohol outcomes (i.e., alcohol use, heavy drinking, and alcohol-related problems) as mediated by alcohol expectancies of social facilitation. Participants were 1347 (men = 660) newly married individuals recruited from the community. They were assessed at the time of marriage and through the 4th wedding anniversary. Longitudinal mediation across time was evaluated using latent growth modeling. Overall, the prospective association between the number of drinking buddies in the social network and all three alcohol outcomes were mediated by alcohol expectancies. In testing group invariance across genders, findings suggest that social facilitation expectancies may be more relevant to men as compared to women in predicting typical alcohol use and alcohol-related problems. Given that the social network may impact alcohol use at least in part through social expectancies, tailoring alcohol interventions to modify these specific beliefs may be particularly beneficial. In addition, strategies that target a drinker’s social network or their drinking buddies specifically may be useful.
doi:10.1037/a0028909
PMCID: PMC3588170  PMID: 22732054
Drinking buddies; alcohol use; peer influence; expectancies; longitudinal
3.  The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture 
Arthritis and rheumatism  2008;58(2):349-358.
Objective
To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population.
Methods
In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti-CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.
Results
The frequency of SE-containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody–negative RA (P = 0.01, by chi-square test).
Conclusion
HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ~50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.
doi:10.1002/art.23166
PMCID: PMC3726059  PMID: 18240241
4.  The mammalian neocortex new pyramidal neuron: a new conception 
The new cerebral cortex (neocortex) and the new type of pyramidal neuron are mammalian innovations that have evolved for operating their increasing motor capabilities while essentially using analogous anatomical and neural makeups. The human neocortex starts to develop in 6-week-old embryos with the establishment of a primordial cortical organization, which resembles the primitive cortices of amphibian and reptiles. From the 8th to the 15th week of age, new pyramidal neurons, of ependymal origin, are progressively incorporated within this primordial cortex forming a cellular plate that divides its components into those above it (neocortex first layer) and those below it (neocortex subplate zone). From the 16th week of age to birth and postnatally, the new pyramidal neurons continue to elongate functionally their apical dendrite by adding synaptic membrane to incorporate the needed sensory information for operating its developing motor activities. The new pyramidal neuron’ distinguishing feature is the capacity of elongating anatomically and functionally its apical dendrite (its main receptive surface) without losing its original attachment to first layer or the location of its soma and, hence, retaining its essential nature. The number of pyramidal cell functional strata established in the motor cortex increases and reflects each mammalian species motor capabilities: the hedgehog needs two pyramidal cell functional strata to carry out all its motor activities, the mouse 3, cat 4, primates 5 and humans 6. The presence of six pyramidal cell functional strata distinguish the human motor cortex from that of others primates. Homo sapiens represent a new evolutionary stage that have transformed his primate brain for operating his unique motor capabilities, such as speaking, writing, painting, sculpturing and thinking as a premotor activity. Words used in language are the motor expression of thoughts and represent sounds produced by maneuvering the column of expiratory air by coordinated motor quivering as it passes through the larynx, pharynx, mouth, tongue, and lips. Homo sapiens cerebrum has developed new motor centers to communicate mental thoughts (and/or intention) through motor actions.
doi:10.3389/fnana.2013.00051
PMCID: PMC3880895  PMID: 24431992
mammals; motor cortex; new pyramidal neuron; development; cortical layering; human
5.  Developmental Aspects of the Intracerebral Microvasculature and Perivascular Spaces: Insights into Brain Response to Late Life Diseases 
The development of the microvasculature of the human cerebral cortex offers insight into the response of the cerebral cortex to later-life brain injury. We describe the 3 basic and distinct components of the developmental anatomy of the cerebral cortical microvascular system. The first compartment is meningeal and, therefore, extracerebral. In addition to the major venous sinuses, arachnoidal arteries and veins, the pial anastomotic capillary plexus that covers the surface of the developing and adult cerebral cortex represents the source of the penetrating vessels that become the second component, the intracerebral extrinsic microvascular compartment. During embryogenesis, sprouting vascular elements from pial capillaries pierce the brain external glial limiting membrane and penetrate the cortex. These vessels, which eventually differentiate into arterioles and venules, are separated from the cortical tissue by the extravascular Virchow-Robin compartment (V-RC) formed between the internal vascular and the external glial basal laminae. The V-RC remains open to the meningeal interstitial spaces and outside of the blood-brain barrier (BBB), and acts as a prelymphatic drainage system for removal of substances that cannot be transported into the blood or catabolized intracellularly. The third element is the dense intracerebral intrinsic microvascular compartment. Intracerebral capillary vessels sprout from the perforating vessels, penetrate through the Virchow-Robin glial membrane and enter the neuropil. Intracerebral capillaries lack smooth muscle and a V-RC and consist only of endothelial cells separated from the intracerebral space by a basal lamina. Their role as the physiological BBB is the exchange of oxygen, glucose and small molecules. This developmental perspective highlights 3 principles: (a) the V-RC is intimately related to the cortical penetrating arterioles and venules and represents an inefficient proto-lymphatic system that lacks the anatomic and physiological constituents found in lymphatic beds elsewhere in the body; (b) the anatomic contiguity of the V-RC and the penetrating vascular compartment (arterioles and venules) implies that pathology in 1 compartment could lead to dysfunction in the others; and (c) the anatomic localization of the immunological BBB at the level of the penetrating venules might impose constraints on immunologically-mediated transport involving the V-RC.
doi:10.1097/NEN.0b013e31823ac627
PMCID: PMC3227674  PMID: 22082663
Alzheimer disease; Chronic traumatic encephalopathy; Development; Microvascular; Neocortex
6.  Most Common SNPs Associated with Rheumatoid Arthritis in Subjects of European Ancestry Confer Risk of Rheumatoid Arthritis in African-Americans 
Arthritis and Rheumatism  2010;62(12):3547-3553.
Objective
Large-scale genetic association studies have identified over 20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African-Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA in an African-American population.
Methods
27 candidate SNPs were genotyped in 556 autoantibody-positive African-Americans with RA and 791 healthy African-American controls. Odds ratios (OR) and 95% confidence intervals (CI) for each SNP were compared to previously published ORs of RA patients of European ancestry. We then calculated a composite Genetic Risk Score (GRS) for each individual based on the sum of all risk alleles.
Results
There was overlap in the OR and 95% CI between the European and African-American populations in 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) demonstrated an OR in the opposite direction from those reported in RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African-American cases were enriched for the European RA risk alleles relative to controls (p=0.00005).
Conclusion
The majority of RA risk alleles previously validated among European ancestry RA patients showed similar ORs in our population of African-Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African-American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel risk alleles for RA in African-Americans.
doi:10.1002/art.27732
PMCID: PMC3030622  PMID: 21120996
7.  The human brain intracerebral microvascular system: development and structure 
The capillary from the meningeal inner pial lamella play a crucial role in the development and structural organization of the cerebral cortex extrinsic and intrinsic microvascular compartments. Only pial capillaries are capable of perforating through the cortex external glial limiting membrane (EGLM) to enter into the nervous tissue, although incapable of perforating the membrane to exit the brain. Circulatory dynamics and functional demands determine which capillaries become arterial and which capillaries become venous. The perforation of the cortex EGLM by pial capillaries is a complex process characterized by three fundamental stages: (1) pial capillary contact with the EGLM with fusion of vascular and glial basal laminae at the contact site, (2) endothelial cell filopodium penetration through the fussed laminae with the formation of a funnel between them that accompanies it into the nervous tissue while remaining open to the meningeal interstitium and, (3) penetration of the whole capillary carrying the open funnel with it and establishing an extravascular Virchow-Robin Compartment (V-RC) that maintains the perforating vessel extrinsic (outside) the nervous tissue through its entire length. The V-RC is walled internally by the vascular basal lamina and externally by the basal lamina of joined glial cells endfeet. The VRC outer glial wall appear as an extension of the cortex superficial EGLM. All the perforating vessels within the V-RCs constitute the cerebral cortex extrinsic microvascular compartment. These perforating vessels are the only one capable of responding to inflammatory insults. The V-RC remains open (for life) to the meningeal interstitium permitting the exchanges of fluid and of cells between brain and meninges. The V-RC function as the brain sole drainage (prelymphatic) system in both physiological as well as pathological situations. During cortical development, capillaries emerge from the perforating vessels, by endothelial cells growing sprouts analogous to their angiogenesis, entering into their corresponding V-RCs. These new capillaries to enter into the nervous tissue must perforate through the V-RC outer glial wall, a process analogous to the original perforation of the cortex EGLM by pial capillaries. These emerging capillaries are incapable of reentering the V-RCs and/or perforating vessels. As the new capillary enters into the nervous tissue, it becomes surrounded by glial endfeet and carries a single basal lamina (possibly glial). Capillaries emerging from contiguous perforators establish an anastomotic plexus between them, by mechanisms still poorly understood. The capillaries of this anastomotic plexus constitute the cerebral cortex intrinsic microvascular compartment and together constitute the so-called blood-brain-barrier. The intrinsic capillaries are changing and readapting continuously, by both active angiogenesis and reabsorption, to the gray matter neurons developmental and functional needs. The brain intrinsic capillaries are among the most active microvessels of the human body. Unresolved developmental and functional aspects concerning the cerebral cortex intrinsic capillary plexus need to be further investigated.
doi:10.3389/fnana.2012.00038
PMCID: PMC3440694  PMID: 22993505
EGLM; endothelial cell filopodium; human brain; intracerebral microvascular system; meningeal inner pial lamella
8.  Comparing self-reported ethnicity to genetic background measures in the context of the Multi-Ethnic Study of Atherosclerosis (MESA) 
BMC Genetics  2011;12:28.
Background
Questions remain regarding the utility of self-reported ethnicity (SRE) in genetic and epidemiologic research. It is not clear whether conditioning on SRE provides adequate protection from inflated type I error rates due to population stratification and admixture. We address this question using data obtained from the Multi-Ethnic Study of Atherosclerosis (MESA), which enrolled individuals from 4 self-reported ethnic groups. We compare the agreement between SRE and genetic based measures of ancestry (GBMA), and conduct simulation studies based on observed MESA data to evaluate the performance of each measure under various conditions.
Results
Four clusters are identified using 96 ancestry informative markers. Three of these clusters are well delineated, but 30% of the self-reported Hispanic-Americans are misclassified. We also found that MESA SRE provides type I error rates that are consistent with the nominal levels. More extensive simulations revealed that this finding is likely due to the multi-ethnic nature of the MESA. Finally, we describe situations where SRE may perform as well as a GBMA in controlling the effect of population stratification and admixture in association tests.
Conclusions
The performance of SRE as a control variable in genetic association tests is more nuanced than previously thought, and may have more value than it is currently credited with, especially when smaller replication studies are being considered in multi-ethnic samples.
doi:10.1186/1471-2156-12-28
PMCID: PMC3068121  PMID: 21375750
9.  The Case for Examining and Treating the Combined Effects of Parental Drug Use and Interparental Violence on Children in their Homes 
This review examines what have been, to this point, generally two divergent lines of research: (a) effects of parental drug abuse on children, and (b) effects of children’s exposure to interparental violence. A small, but growing body of literature has documented the robust relationship between drug use and intimate partner violence. Despite awareness of the interrelationship, little attention has been paid to the combined effect of these deleterious parent behaviors on children in these homes. Thus, we argue for the need to examine the developmental impact of these behaviors (both individually and combined) on children in these homes and for treatment development to reflect how each of these parent behaviors may affect children of substance abusers.
doi:10.1016/j.avb.2009.09.002
PMCID: PMC2796845  PMID: 20161505
Children of Substance Abusers; Parental Drug Abuse Interparental Violence
10.  An Examination of the Association of Selected Toxic Metals with Total and Central Obesity Indices: NHANES 99-02 
It is conceivable that toxic metals contribute to obesity by influencing various aspects of metabolism, such as by substituting for essential micronutrients and vital metals, or by inducing oxidative stress. Deficiency of the essential metal zinc decreases adiposity in humans and rodent models, whereas deficiencies of chromium, copper, iron, and magnesium increases adiposity. This study utilized the NHANES 99-02 data to explore the association between waist circumference and body mass index with the body burdens of selected toxic metals (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten). Some of the associations were significant direct relationships (barium and thallium), and some of the associations were significant inverse relationships (cadmium, cobalt, cesium, and lead). Molybdenum, antimony, and tungsten had mostly insignificant associations with waist circumference and body mass index. This is novel result for most of the toxic metals studied, and a surprising result for lead because high stored lead levels have been shown to correlate with higher rates of diabetes, and obesity may be a key risk factor for developing diabetes. These associations suggest the possibility that environmental exposure to metals may contribute to variations in human weight gain/loss. Future research, such as prospective studies rather than the cross-sectional studies presented here, is warranted to confirm these findings.
doi:10.3390/ijerph7093332
PMCID: PMC2954548  PMID: 20948927
obesity; endocrine disruptors; waist circumference; toxic metals; public health
11.  Endocrine Disruptors and Obesity: An Examination of Selected Persistent Organic Pollutants in the NHANES 1999–2002 Data 
Recent evidence suggests that endocrine disrupting chemicals (EDCs) may cause perturbations in endogenous hormonal regulation that predispose to weight gain. Using data from NHANES (1999–2002), we investigated the association between body mass index (BMI), waist circumference (WC) and selected persistent organic pollutants (POPs) via multiple linear regressions. Consistent interaction was found between gender, ln oxychlordane and ln p,p’ DDT. Also, we found an association between WC and ln oxychlordane and ln hpcdd in subjects with detectable levels of POPs, whereas an association between WC and ln p,p’ DDT was observed in all subjects. Furthermore, ln Ocdd showed an increase with higher WC and BMI, whereas, ln trans-nonachlor decreased with higher BMI. Hence, BMI and WC are associated with POPs levels, making the chemicals plausible contributors to the obesity epidemic.
doi:10.3390/ijerph7072988
PMCID: PMC2922741  PMID: 20717554
Obesity; endocrine disruptors; waist circumference; persistent organic pollutants; public health
12.  Multiple Imputation to Correct for Measurement Error in Admixture Estimates in Genetic Structured Association Testing 
Human Heredity  2009;68(1):65-72.
Objectives
Structured association tests (SAT), like any statistical model, assumes that all variables are measured without error. Measurement error can bias parameter estimates and confound residual variance in linear models. It has been shown that admixture estimates can be contaminated with measurement error causing SAT models to suffer from the same afflictions. Multiple imputation (MI) is presented as a viable tool for correcting measurement error problems in SAT linear models with emphasis on correcting measurement error contaminated admixture estimates.
Methods
Several MI methods are presented and compared, via simulation, in terms of controlling Type I error rates for both non-additive and additive genotype coding.
Results
Results indicate that MI using the Rubin or Cole method can be used to correct for measurement error in admixture estimates in SAT linear models.
Conclusion
Although MI can be used to correct for admixture measurement error in SAT linear models, the data should be of reasonable quality, in terms of marker informativeness, because the method uses the existing data to borrow information in which to make the measurement error corrections. If the data are of poor quality there is little information to borrow to make measurement error corrections.
doi:10.1159/000210450
PMCID: PMC2716289  PMID: 19339787
Multiple imputation; Measurement error; Admixture; Ancestry; Structured association testing
13.  The use of plasmodes as a supplement to simulations: A simple example evaluating individual admixture estimation methodologies 
With the advent of powerful computers, simulation studies are becoming an important tool in statistical methodology research. However, computer simulations of a specific process are only as good as our understanding of the underlying mechanisms. An attractive supplement to simulations is the use of plasmode datasets. Plasmodes are data sets that are generated by natural biologic processes, under experimental conditions that allow some aspect of the truth to be known. The benefit of the plasmode approach is that the data are generated through completely natural processes, thus circumventing the common concern of the realism and accuracy of computer simulated data. The estimation of admixture, or the proportion of an individual’s genome that originates from different founding populations, is a particularly difficult research endeavor that is well suited to the use of plasmodes. Current methods have been tested with simulations of complex populations where the underlying mechanisms such as the rate and distribution of recombination are not well understood. To demonstrate the utility of this method data derived from mouse crosses is used to evaluate the effectiveness of several admixture estimation methodologies. Each cross shares a common founding population so that the ancestry proportion for each individual is known, allowing for the comparison of true and estimated individual admixture values. Analysis shows that the different estimation methodologies (Structure, AdmixMap and FRAPPE) examined all perform well with simple datasets. However, the performance of the estimation methodologies varied greatly when applied to a plasmode consisting of three founding populations. The results of these examples illustrate the utility of plasmodes in the evaluation of statistical genetics methodologies.
doi:10.1016/j.csda.2008.02.032
PMCID: PMC2678733  PMID: 20161321
Admixture; ancestry; simulation; plasmode; population structure
14.  Review and Evaluation of Methods Correcting for Population Stratification with a Focus on Underlying Statistical Principles 
Human heredity  2008;66(2):67-86.
When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.
doi:10.1159/000119107
PMCID: PMC2803696  PMID: 18382087
Admixture; Ancestry; Association; Covariance-based tests; Genomic control; Linkage; Marginal-based tests; QTL; RAM; Randomization; SAT; Structure; Sufficient statistics; TDT
16.  Missing Data in Randomized Clinical Trials for Weight Loss: Scope of the Problem, State of the Field, and Performance of Statistical Methods 
PLoS ONE  2009;4(8):e6624.
Background
Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods.
Methodology/Principal Findings
We searched PubMed and Cochrane databases (2000–2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e−λt) where λ was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive.
Conclusion/Significance
Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.
doi:10.1371/journal.pone.0006624
PMCID: PMC2720539  PMID: 19675667
17.  Multiple Imputation to Correct for Measurement Error in Admixture Estimates in Genetic Structured Association Testing 
Human heredity  2009;68(1):65-72.
Objectives:
Structured association tests (SAT), like any statistical model, assumes that all variables are measured without error. Measurement error can bias parameter estimates and confound residual variance in linear models. It has been shown that admixture estimates can be contaminated with measurement error causing SAT models to suffer from the same afflictions. Multiple imputation (MI) is presented as a viable tool for correcting measurement error problems in SAT linear models with emphasis on correcting measurement error contaminated admixture estimates.
Methods:
Several MI methods are presented and compared, via simulation, in terms of controlling Type I error rates for both non-additive and additive genotype coding.
Results:
Results indicate that MI using the Rubin or Cole method can be used to correct for measurement error in admixture estimates in SAT linear models.
Conclusion:
Although MI can be used to correct for admixture measurement error in SAT linear models, the data should be of reasonable quality, in terms of marker informativeness, because the method uses the existing data to borrow information in which to make the measurement error corrections. If the data are of poor quality there is little information to borrow to make measurement error corrections.
doi:10.1159/000210450
PMCID: PMC2716289  PMID: 19339787
Multiple imputation; Measurement error; Admixture; Ancestry; Structured association testing
18.  An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans 
PLoS Genetics  2009;5(3):e1000424.
Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
Author Summary
Rheumatoid arthritis (RA) is a systemic autoimmune condition affecting the synovial membranes of diarthrodial joints. The etiology of RA is unclear but is thought to result from an environmental trigger in the context of genetic predisposition. We report that a single nucleotide polymorphism (SNP) (rs231778) in CTLA4, which encodes a negative regulator of T cell activation, is associated (p = 2.4×10−28) with protection from developing RA among African Americans. rs231778 is only polymorphic in populations of African ancestry. Protective alleles such as this one may contribute to the purported lower prevalence of RA in African Americans. Our finding appears to be independent from confounding by linkage with the HLA-DRB1 shared epitope or by genetic admixture. Furthermore, we did not replicate associations of CTLA4 SNPs with RA or other autoimmune diseases previously reported in Asians and Caucasians, such as rs3087243 (+60C/T) and rs231775 (+49A/G). The associations of different SNPs with RA susceptibility specific to different populations highlight the importance of CTLA4 in the pathogenesis of RA and demonstrate the ethnic-specific genetic background that contributes to its susceptibility.
doi:10.1371/journal.pgen.1000424
PMCID: PMC2652071  PMID: 19300490
19.  Review and Evaluation of Methods Correcting for Population Stratification with a Focus on Underlying Statistical Principles 
Human Heredity  2008;66(2):67-86.
When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.
doi:10.1159/000119107
PMCID: PMC2803696  PMID: 18382087
Admixture; Ancestry; Association; Covariance-based tests; Genomic control; Linkage; Marginal-based tests; QTL; RAM; Randomization; SAT; Structure; Sufficient statistics; TDT
20.  Commonality of functional annotation: a method for prioritization of candidate genes from genome-wide linkage studies† 
Nucleic Acids Research  2008;36(4):e26.
Linkage studies of complex traits frequently yield multiple linkage regions covering hundreds of genes. Testing each candidate gene from every region is prohibitively expensive and computational methods that simplify this process would benefit genetic research. We present a new method based on commonality of functional annotation (CFA) that aids dissection of complex traits for which multiple causal genes act in a single pathway or process. CFA works by testing individual Gene Ontology (GO) terms for enrichment among candidate gene pools, performs multiple hypothesis testing adjustment using an estimate of independent tests based on correlation of GO terms, and then scores and ranks genes annotated with significantly-enriched terms based on the number of quantitative trait loci regions in which genes bearing those annotations appear. We evaluate CFA using simulated linkage data and show that CFA has good power despite being conservative. We apply CFA to published linkage studies investigating age-of-onset of Alzheimer's disease and body mass index and obtain previously known and new candidate genes. CFA provides a new tool for studies in which causal genes are expected to participate in a common pathway or process and can easily be extended to utilize annotation schemes in addition to the GO.
doi:10.1093/nar/gkn007
PMCID: PMC2275105  PMID: 18263617
21.  Type I Error Rates For A One Factor Within-Subjects Design With Missing Values 
Missing data are a common problem in educational research. A promising technique, that can be implemented in SAS PROC MIXED and is therefore widely available, is to use maximum likelihood to estimate model parameters and base hypothesis tests on these estimates. However, it is not clear which test statistic in PROC MIXED performs better with missing data. The performance of the Hotelling-Lawley-McKeon and Kenward-Roger omnibus test statistics on the means for a single factor within-subject ANOVA are compared. The results indicate that the Kenward-Roger statistic performed better in terms of keeping the Type I error close to the nominal alpha level.
PMCID: PMC1502378  PMID: 16845436
Type I error; Within-subjects; missing values; Kenward-Roger omnibus test; robustness
22.  Regional Admixture Mapping and Structured Association Testing: Conceptual Unification and an Extensible General Linear Model 
PLoS Genetics  2006;2(8):e137.
Individual genetic admixture estimates, determined both across the genome and at specific genomic regions, have been proposed for use in identifying specific genomic regions harboring loci influencing phenotypes in regional admixture mapping (RAM). Estimates of individual ancestry can be used in structured association tests (SAT) to reduce confounding induced by various forms of population substructure. Although presented as two distinct approaches, we provide a conceptual framework in which both RAM and SAT are special cases of a more general linear model. We clarify which variables are sufficient to condition upon in order to prevent spurious associations and also provide a simple closed form “semiparametric” method of evaluating the reliability of individual admixture estimates. An estimate of the reliability of individual admixture estimates is required to make an inherent errors-in-variables problem tractable. Casting RAM and SAT methods as a general linear model offers enormous flexibility enabling application to a rich set of phenotypes, populations, covariates, and situations, including interaction terms and multilocus models. This approach should allow far wider use of RAM and SAT, often using standard software, in addressing admixture as either a confounder of association studies or a tool for finding loci influencing complex phenotypes in species as diverse as plants, humans, and nonhuman animals.
Synopsis
In recent years, scientific efforts to find genes influencing disease and health-related traits have sought to capitalize on the unique genetic characteristics of admixed populations. Admixture can refer to the event of two or more genetically diverse populations intermating and producing an admixed population. Admixture creates the potential for efficient identification of trait-influencing genes. However, genetic association studies using admixed populations are also prone to incorrectly concluding that a gene is linked and associated with a trait even when it is not. Several researchers have produced promising statistical methodologies for genetic association studies within admixed populations. In this paper, the authors show how these statistical methods can be unified in a broadly applicable regression framework and discuss which variables should be included in the regression models for valid testing. Because the variables required in this regression framework can only be measured with error, the authors show the consequences of these measurement errors and present measurement error correction methods applicable to this problem. By recasting the statistical methods for genetic association studies within admixed populations as regression models, a broader range of modeling and hypothesis testing becomes available.
doi:10.1371/journal.pgen.0020137
PMCID: PMC1557785  PMID: 16934005

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