The Effects of Social, Personal, and Behavioral Risk Factors and PM2.5 on Cardio-Metabolic Disparities in a Cohort of Community Health Center Patients.

(1) Background: Cardio-metabolic diseases (CMD), including cardiovascular disease, stroke, and diabetes, have numerous common individual and environmental risk factors. Yet, few studies to date have considered how these multiple risk factors together affect CMD disparities between Blacks and Whites. (2) Methods: We linked daily fine particulate matter (PM2.5) measures with survey responses of participants in the Southern Community Cohort Study (SCCS). Generalized linear mixed modeling (GLMM) was used to estimate the relationship between CMD risk and social-demographic characteristics, behavioral and personal risk factors, and exposure levels of PM2.5. (3) Results: The study resulted in four key findings: (1) PM2.5 concentration level was significantly associated with reported CMD, with risk rising by 2.6% for each µg/m3 increase in PM2.5; (2) race did not predict CMD risk when clinical, lifestyle, and environmental risk factors were accounted for; (3) a significant variation of CMD risk was found among participants across states; and (4) multiple personal, clinical, and social-demographic and environmental risk factors played a role in predicting CMD occurrence. (4) Conclusions: Disparities in CMD risk among low social status populations reflect the complex interactions of exposures and cumulative risks for CMD contributed by different personal and environmental factors from natural, built, and social environments.

A novel approach to analyzing lung cancer mortality disparities: Using the exposome and a graph-theoretical toolchain.

OBJECTIVES: The aim is to identify exposures associated with lung cancer mortality and mortality disparities by race and gender using an exposome database coupled to a graph theoretical toolchain. METHODS: Graph theoretical algorithms were employed to extract paracliques from correlation graphs using associations between 2162 environmental exposures and lung cancer mortality rates in 2067 counties, with clique doubling applied to compute an absolute threshold of significance. Factor analysis and multiple linear regressions then were used to analyze differences in exposures associated with lung cancer mortality and mortality disparities by race and gender. RESULTS: While cigarette consumption was highly correlated with rates of lung cancer mortality for both white men and women, previously unidentified novel exposures were more closely associated with lung cancer mortality and mortality disparities for blacks, particularly black women. CONCLUSIONS: Exposures beyond smoking moderate lung cancer mortality and mortality disparities by race and gender. POLICY IMPLICATIONS: An exposome approach and database coupled with scalable combinatorial analytics provides a powerful new approach for analyzing relationships between multiple environmental exposures, pathways and health outcomes. An assessment of multiple exposures is needed to appropriately translate research findings into environmental public health practice and policy.

Exploration of preterm birth rates using the public health exposome database and computational analysis methods.

Recent advances in informatics technology has made it possible to integrate, manipulate, and analyze variables from a wide range of scientific disciplines allowing for the examination of complex social problems such as health disparities. This study used 589 county-level variables to identify and compare geographical variation of high and low preterm birth rates. Data were collected from a number of publically available sources, bringing together natality outcomes with attributes of the natural, built, social, and policy environments. Singleton early premature county birth rate, in counties with population size over 100,000 persons provided the dependent variable. Graph theoretical techniques were used to identify a wide range of predictor variables from various domains, including black proportion, obesity and diabetes, sexually transmitted infection rates, mother's age, income, marriage rates, pollution and temperature among others. Dense subgraphs (paracliques) representing groups of highly correlated variables were resolved into latent factors, which were then used to build a regression model explaining prematurity (R-squared = 76.7%). Two lists of counties with large positive and large negative residuals, indicating unusual prematurity rates given their circumstances, may serve as a starting point for ways to intervene and reduce health disparities for preterm births.

Scalable combinatorial tools for health disparities research.

Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual's genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject.

Differential Shannon entropy and differential coefficient of variation: alternatives and augmentations to differential expression in the search for disease-related genes.

Differential expression has been a standard tool for analysing case-control transcriptomic data since the advent of microarray technology. It has proved invaluable in characterising the molecular mechanisms of disease. Nevertheless, the expression profile of a gene across samples can be perturbed in ways that leave the expression level unaltered, while a biological effect is nonetheless present. This paper describes and analyses differential Shannon entropy and differential coefficient of variation, two alternate techniques for identifying genes of interest. Ontological analysis across 16 human disease datasets demonstrates that these alternatives are effective at identifying disease-related genes not found by mere differential expression alone. Because the two alternate techniques are based on somewhat different mathematical formulations, they tend to produce somewhat different gene lists. Moreover, each may pinpoint genes completely overlooked by the other. Thus, measures of entropy and variation can be used to replace or better yet augment standard differential expression computations.

On finding bicliques in bipartite graphs: a novel algorithm and its application to the integration of diverse biological data types.

BACKGROUND: Integrating and analyzing heterogeneous genome-scale data is a huge algorithmic challenge for modern systems biology. Bipartite graphs can be useful for representing relationships across pairs of disparate data types, with the interpretation of these relationships accomplished through an enumeration of maximal bicliques. Most previously-known techniques are generally ill-suited to this foundational task, because they are relatively inefficient and without effective scaling. In this paper, a powerful new algorithm is described that produces all maximal bicliques in a bipartite graph. Unlike most previous approaches, the new method neither places undue restrictions on its input nor inflates the problem size. Efficiency is achieved through an innovative exploitation of bipartite graph structure, and through computational reductions that rapidly eliminate non-maximal candidates from the search space. An iterative selection of vertices for consideration based on non-decreasing common neighborhood sizes boosts efficiency and leads to more balanced recursion trees. RESULTS: The new technique is implemented and compared to previously published approaches from graph theory and data mining. Formal time and space bounds are derived. Experiments are performed on both random graphs and graphs constructed from functional genomics data. It is shown that the new method substantially outperforms the best previous alternatives. CONCLUSIONS: The new method is streamlined, efficient, and particularly well-suited to the study of huge and diverse biological data. A robust implementation has been incorporated into GeneWeaver, an online tool for integrating and analyzing functional genomics experiments, available at http://geneweaver.org. The enormous increase in scalability it provides empowers users to study complex and previously unassailable gene-set associations between genes and their biological functions in a hierarchical fashion and on a genome-wide scale. This practical computational resource is adaptable to almost any applications environment in which bipartite graphs can be used to model relationships between pairs of heterogeneous entities.

The maximum clique enumeration problem: algorithms, applications, and implementations.

BACKGROUND: The maximum clique enumeration (MCE) problem asks that we identify all maximum cliques in a finite, simple graph. MCE is closely related to two other well-known and widely-studied problems: the maximum clique optimization problem, which asks us to determine the size of a largest clique, and the maximal clique enumeration problem, which asks that we compile a listing of all maximal cliques. Naturally, these three problems are NP-hard, given that they subsume the classic version of the NP-complete clique decision problem. MCE can be solved in principle with standard enumeration methods due to Bron, Kerbosch, Kose and others. Unfortunately, these techniques are ill-suited to graphs encountered in our applications. We must solve MCE on instances deeply seeded in data mining and computational biology, where high-throughput data capture often creates graphs of extreme size and density. MCE can also be solved in principle using more modern algorithms based in part on vertex cover and the theory of fixed-parameter tractability (FPT). While FPT is an improvement, these algorithms too can fail to scale sufficiently well as the sizes and densities of our datasets grow. RESULTS: An extensive testbed of benchmark graphs are created using publicly available transcriptomic datasets from the Gene Expression Omnibus (GEO). Empirical testing reveals crucial but latent features of such high-throughput biological data. In turn, it is shown that these features distinguish real data from random data intended to reproduce salient topological features. In particular, with real data there tends to be an unusually high degree of maximum clique overlap. Armed with this knowledge, novel decomposition strategies are tuned to the data and coupled with the best FPT MCE implementations. CONCLUSIONS: Several algorithmic improvements to MCE are made which progressively decrease the run time on graphs in the testbed. Frequently the final runtime improvement is several orders of magnitude. As a result, instances which were once prohibitively time-consuming to solve are brought into the domain of realistic feasibility.

The effect of surgical preparation technique on the bacterial load of surgical needles and suture material used during strabismus surgery.

PURPOSE: To investigate the effectiveness of 3 surgical preparation techniques in decreasing bacterial contamination of needles and suture material during strabismus surgery. METHODS: Consecutive patients requiring 2-muscle strabismus surgery were randomized into 1 of 3 groups. In Group A, patients' periocular skin and bulbar conjunctivae underwent preparation with 5% povidone-iodine; the drape was placed without regard to eyebrows; and an open wire-loop lid speculum was used. Group B patients underwent the same preparation as Group A patients; however, the eyelashes and eyebrows were scrubbed with 5% povidone-iodine on cotton tip applicators, and the drape was placed to exclude the eyebrows from the surgical field. Group C patients underwent the same preparation as Group B patients; however, a bladed lid speculum was used during surgery to exclude some of the eyelashes from the surgical field. After the procedure, all needles and suture materials were sent separately for aerobic culture. The data were analyzed for differences in contamination rates between the groups. RESULTS: Of 77 patients, 24 (31.4%) had either a needle and/or suture contaminant. Groups A, B, and C had mean contamination rates of 29.6%, 34.6%, and 29.2%, respectively. There was no significant statistical variation in contamination among the 3 groups. The most common organism identified was a coagulase-negative staphylococcus strain. CONCLUSIONS: More meticulous sterile preparation of the surgical field did not result in a meaningful reduction in suture or needle contamination rates during strabismus surgery.

Treatment of symptomatic convergence insufficiency with a home-based computer orthoptic exercise program.

PURPOSE: To determine the efficacy of a home-based computer orthoptic program to treat symptomatic convergence insufficiency. METHODS: A retrospective review of consecutive patients with symptomatic convergence insufficiency treated with a home-based computer orthoptic program was performed. Symptomatic convergence insufficiency was defined as: near point of convergence (NPC) >6 cm, decreased positive fusional vergence, exophoria at near at least 4(Δ) greater than at far, and documented complaints of asthenopia, diplopia, or headaches with reading or near work. The Computer Orthoptics CVS program was used for this study. Before beginning the computer orthoptic program, patients with an NPC >50 cm were given 4 base-in prisms and push-up exercises (NPC exercises with an accommodative target) for 2 weeks. RESULTS: A total of 42 patients were included. Mean treatment duration was 12.6 weeks; mean follow-up, 8.5 months. Of the 42 patients, 35 were treated with the home-based computer orthoptic program and push-up exercises; the remaining 7 only used the computer orthoptic program. Because of a remote NPC, 5 patients were given base-in Fresnel prism before starting treatment. Baseline mean NPC was 24.2 cm; posttreatment mean NPC improved to 5.6 cm: 39 patients (92.8%) achieved an NPC of ≤6 cm (p < 0.001). Positive fusional vergence improved in 39 patients (92.8%). Fourteen patients reduced their near exophoria by ≥5(Δ). A total of 27 patients (64.2%) reported resolution of symptoms after treatment. CONCLUSIONS: In our study, home-based computer orthoptic exercises reduced symptoms and improved NPC and fusional amplitudes. The computer orthoptic program is an effective option for treating symptomatic convergence insufficiency.

Neural circuit involved in idiopathic infantile nystagmus syndrome based on FMRI.

PURPOSE: To identify the neural circuitry of idiopathic infantile nystagmus syndrome (INS), characterized by an early onset alternating series of slow and rapid eye movements that can manifest in different waveforms and genetic lines. The neural circuitry of INS is currently unknown. METHODS: A novel functional magnetic resonance imaging (fMRI) method, referred to as the null zone fMRI technique, was used to identify the neural circuitry for INS. In the null zone fMRI technique, a gaze position with minimal nystagmus within the null zone was linked to the fMRI "off" condition and a gaze position with robust nystagmus outside of the null zone was linked to the fMRI "on" condition. Eye movements were monitored with an fMRI compatible eye tracker and observed in real time to ensure subject compliance in "on" and "off" states. Subjects with INS (n = 4) included three family members (a mother and two daughters) with presumed autosomal dominant INS, as well as age- and gender-matched normal controls (n = 3). RESULTS: Three of four subjects with INS demonstrated significant increased activation of the declive of the cerebellum, whereas no normal subjects under identical conditions showed activation of the declive of the cerebellum. Both groups showed significant activation in the occipital lobe (Brodmann areas 17, 18, 19, and cuneus). CONCLUSION: A novel fMRI method demonstrated that the declive of the cerebellum is actively involved in INS. These are the first results to identify the cerebellum, and specifically the declive, as a possible site involved in the ocular motor dysfunction known as INS.

Instruction dependent activation during optokinetic nystagmus (OKN) stimulation: An FMRI study at 3T.

Modifying experimental conditions of optokinetic nystagmus (OKN) result in different outcomes and may not optimally translate into clinical testing. The purpose of this study was to assess the influence of subject instruction on the anatomical correlates of OKN. The instructions were to voluntarily look or stare at the same moving grating with fixed contrast and spatial and temporal frequencies. Look and stare OKN were generated under identical stimulus "ON" conditions (vertical sine wave grating of 1.14c/deg drifting right to left at 11.4c/s with binocular viewing). FMRI was undertaken utilizing a 3.0T GE system and the BOLD technique. Subjects included 6 normal adults ranging in age from 18 to 54 years with normal visual acuity (20/20 or better) and normal stereoacuity (40s of arc or better). The results reveal that look OKN generated significantly more cortical FMRI activation than stare OKN. Look OKN areas included the culmen, parahippocampal, lingual, middle temporal gyri, inferior and superior parietal lobules and precuneus, all of which were unilaterally activated in the left hemisphere. The middle occipital gyrus was unilaterally activated in the right hemisphere while the cuneus was bilaterally activated. These results show that the activation sites for OKN studies are dependent on subject instruction which influence the type of OKN generated. Specifically, voluntary look OKN involved more brain sites than stare OKN. In so doing, we illustrate the importance of subject instruction and recommend that FMRI investigators of OKN be cognizant of these effects. The anatomical correlates of the look versus stare are discussed.

Corneal power measurements in fixating versus anesthetized nonfixating children using a handheld keratometer.

PURPOSE: To compare keratometry measurements on a fixating patient with readings from the same nonfixating patient intraoperatively using the Nidek KM-500 handheld keratometer. METHODS: Consecutive patients who were scheduled for strabismus or nasolacrimal surgery between 5 and 11 years of age were included in the study. Handheld keratometry was performed preoperatively on both eyes with the child fixating and intraoperatively with the child anesthetized. Three readings were taken on each eye. The steepest and flattest corneal meridians were recorded. Intraclass correlation coefficients were calculated to assess reliability, and interchangeability was assessed by the use of the Bland-Altman method. RESULTS: Included in the study were 55 eyes of 28 patients. The average fixating keratometry reading was 44.10 +/- 1.45 D for right eyes and 44.12 +/- 1.42 D for left eyes. The average nonfixating keratometry reading was 44.06 +/- 1.62 D for right eyes and 44.02 +/- 1.54 D for left eyes. The intraclass correlation coefficient for the average keratometry obtained fixating versus nonfixating was 0.96 for right eyes and 0.95 for left eyes. The Bland-Altman analysis showed fairly large limits of agreement between readings, but most readings fall within the limits of variability. The mean time to obtain the intraoperative measurements was 4.26 minutes. CONCLUSIONS: In our study the Nidek KM-500 handheld keratometer provided reliable readings when used intraoperatively on anesthetized nonfixating children and required minimal time to perform.

Identifying genetic loci and spleen gene coexpression networks underlying immunophenotypes in BXD recombinant inbred mice.

The immune system plays a pivotal role in the susceptibility to and progression of a variety of diseases. Due to a strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J × DBA/2J) panel of recombinant inbred (RI) mouse strains, provide unique models through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across both multiple studies and time. We performed basic immunophenotyping (e.g., percentage of circulating B and T lymphocytes and CD4(+) and CD8(+) T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the immunophenotypic variation in this strain panel and to characterize the genetic architecture that underlies these traits. Significant QTL models that explained the majority (50-77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4(+):CD8(+) ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts, Ptprk and Acp1, as candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource for prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system.

Percutaneous drainage and ablation of orbital dermoid cysts.

BACKGROUND: Vision-threatening intraorbital dermoid cysts have traditionally been treated by complete surgical resection. Such radical surgical intervention may pose serious risks to both vision acuity and cosmesis. We describe a novel, minimally invasive approach for the treatment of orbital dermoid cysts. METHODS: This is an interventional retrospective case series. Two patients (17 and 4 years) presented with large intraorbital dermoid cysts. The first patient had a dumbbell-shaped lesion involving the temporalis fossa and superotemporal orbit. The second patient had a large, superior intraorbital lesion. Both patients presented with visual disturbance, globe displacement, and eyelid ptosis. A series of techniques were developed and implemented for percutaneous access, drainage, and catheter-based ablation (dual drug technique) of both orbital dermoid cysts. Initial access was gained with a 14-gauge angiocatheter needle system, followed by serial emulsification and drainage of the cyst contents. A 5-French catheter was coaxially placed for fluoroscopic contrast cyst definition and subsequent dual drug chemical ablation (sodium tetradecyl sulfate and ethanol). Suction drainage was maintained for 24 hours following ablation. RESULTS: Radiological and clinical evaluation demonstrated complete resolution of the dermoid cysts with no recurrence at 12-month follow-up in the first patient and 3 months in the second patient. Cosmetic results were excellent. Patients reported no pain and there were no neurologic, oculomotor, infectious, hemorrhagic, or other complications. CONCLUSIONS: Minimally invasive percutaneous drainage and ablation appears to be a promising treatment for large orbital dermoid cysts which would otherwise require extensive surgery to excise. Collaboration of an ophthalmologist and interventional radiologist is essential for evaluation, treatment, and follow-up.