A functional mixed model for scalar on function regression with application to a functional MRI study.

Motivated by a functional magnetic resonance imaging (fMRI) study, we propose a new functional mixed model for scalar on function regression. The model extends the standard scalar on function regression for repeated outcomes by incorporating subject-specific random functional effects. Using functional principal component analysis, the new model can be reformulated as a mixed effects model and thus easily fit. A test is also proposed to assess the existence of the subject-specific random functional effects. We evaluate the performance of the model and test via a simulation study, as well as on data from the motivating fMRI study of thermal pain. The data application indicates significant subject-specific effects of the human brain hemodynamics related to pain and provides insights on how the effects might differ across subjects.

Specific IgE Decision Point Cutoffs in Children with IgE-Mediated Wheat Allergy and a Review of the Literature.

BACKGROUND: Wheat IgE-mediated food allergy in children is one of the most frequent food allergies in westernized countries, affecting between 0.4 and 1% of children. Although 95% predictive decision points have been determined for major allergens such as peanut, egg, and milk, the diagnostic performances of wheat-specific IgE (sIgE) and wheat component testing are not well established. OBJECTIVES: The aim of this study was to determine sIgE decision point cutoffs in children with IgE-mediated wheat allergy and provide a review of the literature. METHOD: A retrospective review of wheat oral food challenges was performed at the pediatric allergy unit of the University Hospitals of Geneva between 2004 and 2019. Performance characteristics for wheat and ω-5 gliadin sIgE were calculated and positive and negative OFC data were compared using the Mann-Whitney U test. RESULTS: A wheat sIgE cutoff of 2.88 kUA/L had a sensitivity of 95% (negative decision point), whereas a cutoff of 78.1 kUA/L had a specificity of 95% (positive decision point). When giving equal weight to sensitivity and specificity, the optimal cutoff point for wheat sIgE was 12 kUA/L, which gave a specificity of 70% and a sensitivity of 66.67%. CONCLUSIONS: These findings suggest a high positive decision point for wheat sIgE (78.1 kUA/L). This reinforces the importance of considering OFC in children with IgE-mediated wheat allergy to confirm diagnosis even in patients with relatively high wheat sIgE values, as there is a risk of falsely mislabeling these patients as allergic.

Identifying and exploiting gene-pathway interactions from RNA-seq data for binary phenotype.

BACKGROUND: RNA sequencing (RNA-seq) technology has identified multiple differentially expressed (DE) genes associated to complex disease, however, these genes only explain a modest part of variance. Omnigenic model assumes that disease may be driven by genes with indirect relevance to disease and be propagated by functional pathways. Here, we focus on identifying the interactions between the external genes and functional pathways, referring to gene-pathway interactions (GPIs). Specifically, relying on the relationship between the garrote kernel machine (GKM) and variance component test and permutations for the empirical distributions of score statistics, we propose an efficient analysis procedure as Permutation based gEne-pAthway interaction identification in binary phenotype (PEA). RESULTS: Various simulations show that PEA has well-calibrated type I error rates and higher power than the traditional likelihood ratio test (LRT). In addition, we perform the gene set enrichment algorithms and PEA to identifying the GPIs from a pan-cancer data (GES68086). These GPIs and genes possibly further illustrate the potential etiology of cancers, most of which are identified and some external genes and significant pathways are consistent with previous studies. CONCLUSIONS: PEA is an efficient tool for identifying the GPIs from RNA-seq data. It can be further extended to identify the interactions between one variable and one functional set of other omics data for binary phenotypes.

Variance component score test for time-course gene set analysis of longitudinal RNA-seq data.

As gene expression measurement technology is shifting from microarrays to sequencing, the statistical tools available for their analysis must be adapted since RNA-seq data are measured as counts. It has been proposed to model RNA-seq counts as continuous variables using nonparametric regression to account for their inherent heteroscedasticity. In this vein, we propose tcgsaseq, a principled, model-free, and efficient method for detecting longitudinal changes in RNA-seq gene sets defined a priori. The method identifies those gene sets whose expression varies over time, based on an original variance component score test accounting for both covariates and heteroscedasticity without assuming any specific parametric distribution for the (transformed) counts. We demonstrate that despite the presence of a nonparametric component, our test statistic has a simple form and limiting distribution, and both may be computed quickly. A permutation version of the test is additionally proposed for very small sample sizes. Applied to both simulated data and two real datasets, tcgsaseq is shown to exhibit very good statistical properties, with an increase in stability and power when compared to state-of-the-art methods ROAST (rotation gene set testing), edgeR, and DESeq2, which can fail to control the type I error under certain realistic settings. We have made the method available for the community in the R package tcgsaseq.

Global analysis of methylation profiles from high resolution CpG data.

New high throughput technologies are now enabling simultaneous epigenetic profiling of DNA methylation at hundreds of thousands of CpGs across the genome. A problem of considerable practical interest is identification of large scale, global changes in methylation that are associated with environmental variables, clinical outcomes, or other experimental conditions. However, there has been little statistical research on methods for global methylation analysis using technologies with individual CpG resolution. To address this critical gap in the literature, we develop a new strategy for global analysis of methylation profiles using a functional regression approach wherein we approximate either the density or the cumulative distribution function (CDF) of the methylation values for each individual using B-spline basis functions. The spline coefficients for each individual are allowed to summarize the individual's overall methylation profile. We then test for association between the overall distribution and a continuous or dichotomous outcome variable using a variance component score test that naturally accommodates the correlation between spline coefficients. Simulations indicate that our proposed approach has desirable power while protecting type I error. The method was applied to detect methylation differences, both genome wide and at LINE1 elements, between the blood samples from rheumatoid arthritis patients and healthy controls and to detect the epigenetic changes of human hepatocarcinogenesis in the context of alcohol abuse and hepatitis C virus infection. A free implementation of our methods in the R language is available in the Global Analysis of Methylation Profiles (GAMP) package at http://research.fhcrc.org/wu/en.html.

Component-resolved analysis of IgA, IgE, and IgG4 during egg OIT identifies markers associated with sustained unresponsiveness.

BACKGROUND: In a previously reported CoFAR study, 55 subjects with egg allergy underwent randomized, placebo-controlled egg oral immunotherapy (eOIT). Active treatment induced desensitization in most and sustained unresponsiveness (SU) in a smaller subset. We hypothesized that component-resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU in OIT subjects. METHODS: Longitudinal samples for 51 egg-allergic subjects (37 active and 14 placebo) were available. Egg white (EW)-, ovalbumin (OVA)-, and ovomucoid (OVM)-specific levels of IgA, IgA1, and IgA2 were quantified by ELISA. IgE and IgG4 to these antigens were quantified using ImmunoCAP® . Clinical responders achieved SU to egg; all others were considered nonresponders. Between-group comparisons were made among active and placebo, as well as responders and nonresponders. RESULTS: No placebo subjects achieved responder status. Through month 48, among the 37 active subjects, baseline IgE-OVM was lower in responders (median 3.97 kU/l, n = 19) than in nonresponders (10.9 kU/l, n = 18, P = 0.010). Logistic regression analysis revealed that lower baseline IgE-EW (P = 0.038), IgE-OVM (P = 0.032), and a higher IgG4/IgE-OVM ratio (P = 0.013) were associated with clinical response. Relative increases in IgG4-EW, IgA-EW, and IgA2-EW were observed in responders (P = 0.024, 0.024, and 0.029, respectively). IgG4/IgE, IgA/IgE, and IgA2/IgE ratios for EW and IgA/IgE ratio for OVA were found to be significantly elevated among responders (P = 0.004, 0.009, 0.028, and 0.008, respectively). CONCLUSIONS: Increased IgG4-EW, IgA-EW, and IgA2-EW during eOIT are associated with clinical response to eOIT. Lower pretreatment IgE-EW and IgE-OVM are also associated with SU. Future studies are needed to evaluate and validate these potential biomarkers.

Allergen Component Testing: Key in Diagnosing Atypical Pollen-Food Allergy Syndrome.

This case report details the complex presentation, diagnosis, and management of a teenager with pollen-food allergen syndrome (PFAS), formerly known as oral allergy syndrome. PFAS, mediated by immunoglobulin E (IgE) antibodies, stems from the cross-reactivity between pollens and uncooked plant-based foods, leading to a spectrum of symptoms, such as itching or tingling of the oral cavity. A UK survey indicated an average PFAS prevalence of 2%, with apples, hazelnuts, and kiwifruit commonly implicated. The presented case involved a 15-year-old girl referred from the respiratory clinic to the allergy clinic due to episodes of sore throat and urticaria rash following Nutella (chocolate paste containing hazelnut) and peanut consumption. Extensive diagnostic measures, including specific IgE testing, skin prick tests, and allergen component testing, revealed cross-reactivity between Bet v 1 and hazelnut allergens. The patient's atopic history, encompassing poorly controlled asthma, allergic rhinitis, and eczema, added layers of complexity to the diagnosis. Management strategies comprised dietary advice, allergen avoidance, and potential consideration of aeroallergen immunotherapy. A comprehensive dietary plan emphasized abstaining from specific foods and raising awareness of potential reactions. The patient, following guidance from the allergy clinic, exhibited improvements in allergic rhinitis and oral symptoms. This case underscores the importance of allergen component testing in diagnosing atypical PFAS presentations and tailoring management plans. Ongoing collaboration between healthcare providers, detailed patient education, and regular follow-ups are crucial for effective PFAS management and long-term care.

Pediatric oral food challenges in the outpatient setting: A single-center experience.

Background: Oral food challenge (OFC) is the criterion standard for diagnosing food allergy (FA). It is important to have parameters to aid in selecting ideal OFC candidates. Objective: We sought to characterize outcomes and predictors of OFCs for common food allergens. Methods: We completed a retrospective chart review of all OFCs for IgE-mediated FA performed at Duke University pediatric allergy clinics from June 2017 through May 2022. Patients were deemed eligible for milk, egg, and nut OFC if testing revealed a specific IgE level not exceeding 2 kU/L and a skin prick test (SPT) resulting in a wheal size not exceeding 5 mm. Different parameters were followed for selecting candidates for baked challenge. Results: A total of 663 OFCs were conducted on 510 patients (59% male). The most common foods challenged were peanut (26%), plain egg (23%), baked egg (8%), and milk (8%), with pass rates of 84%, 88%, 62%, and 84%, respectively. Of the patients who failed OFC, 84% had objective symptoms, 23% had multisystemic reactions, and 15% required epinephrine. Although the presence of a personal or family history of atopy or prior failed OFC was not associated with outcomes, a history of anaphylaxis (regardless of the trigger) was associated with increased risk of failure. Conclusion: Although there are no established consensus guidelines, our study provides a benchmark illustrating that cutoffs of a specific IgE level not exceeding 2 kU/L and SPT finding not exceeding 5 mm result in a failure rate of approximately 13% for nonbaked milk, nonbaked egg, and nuts. The high rate of failed baked egg OFCs is likely related to selection bias, but our results illustrate the low negative predictive value of ovomucoid.

Food challenges: Patient selection, predictors, component testing, and decision points.

Background: Oral food challenges are commonly used when there is uncertainty based on a clinical history as to whether a food allergy exists and to assess whether a food allergy has been outgrown. Methods: A narrative review was performed, synthesizing available evidence in the literature. Results: Because food challenges are generally multi-hour procedures that carry the risk for potentially severe allergic reactions, careful patient selection is important. Allergy tests can provide additional supportive information to guide decision-making but do not have sufficient diagnostic accuracy to replace food challenges in most circumstances. Conclusion: Clinical history provides important clues with regard to the likelihood that a reaction may occur and should be combined with patient and family preferences and allergy test results when making decisions about pursuing food challenges.

A novel approach to directly measuring wheel and caster rolling resistance accurately predicts user-wheelchair system-level rolling resistance.

Introduction: Clinical practice guidelines for preservation of upper extremity recommend minimizing wheelchair propulsion forces. Our ability to make quantitative recommendations about the effects of wheelchair configuration changes is limited by system-level tests to measure rolling resistance (RR). We developed a method that directly measures caster and propulsion wheel RR at a component-level. The study purpose is to assess accuracy and consistency of component-level estimates of system-level RR. Methods: The RR of N = 144 simulated unique wheelchair-user systems were estimated using our novel component-level method and compared to system-level RR measured by treadmill drag tests, representing combinations of caster types/diameters, rear wheel types/diameters, loads, and front-rear load distributions. Accuracy was assessed by Bland-Altman limits of agreement (LOA) and consistency by intraclass correlation (ICC). Results: Overall ICC was 0.94, 95% CI [0.91-0.95]. Component-level estimates were systematically lower than system-level (-1.1 N), with LOA +/-1.3 N. RR force differences between methods were constant over the range of test conditions. Conclusion: Component-level estimates of wheelchair-user system RR are accurate and consistent when compared to a system-level test method, evidenced by small absolute LOA and high ICC. Combined with a prior study on precision, this study helps to establish validity for this RR test method.

The Value of Current Laboratory Tests in Diagnosing Food, Venom, and Drug Allergies.

An accurate diagnosis of IgE-mediated allergies is necessary to inform risk management for severe allergic reactions including anaphylaxis for food, venom, and drug allergies. The most widely available laboratory test for allergy is serum-specific IgE testing, which is routinely used for food allergy and insect sting allergy. Testing for specific IgE is limited by high sensitivity and low specificity, resulting in concern regarding overdiagnosis. Testing of allergen components has led to improved diagnosis for some food and venom allergens. Additional options for laboratory tests, such as epitope analysis, basophil activation, and mast cell activation, are being investigated for their potential to optimize diagnosis and provide predictors for reaction severity and treatment response. In contrast, laboratory testing for drug allergy is more limited because to date, there are no well-validated commercial assays in the United States. Furthermore, it is important to diagnose delayed reactions to medications, because these also significantly affect decision-making regarding therapeutic options for infectious disorders. Reliable tests for both immediate and delayed drug hypersensitivity are much needed, because drug allergy labels can significantly limit treatment options for patients. Research in this area is emerging.

Impact of Connector Placement and Design on Bending Stiffness of Spinal Constructs.

OBJECTIVE: To evaluate the stability of multiple rod-connector construct designs using a mechanical 4-point bending testing frame. METHODS: A mechanical study was used to evaluate the bending stiffness of 3 connectors across 12 different configurations of rod-connector-rod constructs. Stability was evaluated in flexion-extension and lateral bending. Combinations of rods having 1 of 3 diameters (4.0 mm, 5.5 mm, and 6.0 mm) connected by 1 of 3 connector types (parallel open, snap-on, and hinged) were compared. Configurations with single connectors and with double connectors with variable spacing were also compared to simulate revision surgery conditions. RESULTS: Constructs consisting of 4.0-mm rods connected to 4.0-mm rods were significantly less stiff as the total number of connectors used in a series exceeded 2. When single-connector configurations were compared, parallel open rod connectors demonstrated greater stiffness in flexion-extension than hinged open connectors, whereas hinged open connectors demonstrated greater stiffness in lateral bending. Using double connectors increased stiffness of 4.0- to 4.0-mm rod configurations in flexion-extension and lateral bending, 4.0- to 6.0-mm rod configurations in flexion-extension, and 5.5- to 6.0-mm rod configurations in lateral bending. Spacing the double connectors significantly improved lateral bending stiffness of 4.0- to 4.0-mm and 5.5- to 6.0-mm rod configurations. CONCLUSIONS: Our data indicate that the design, number, and placement of rod connectors have a significant impact on the bending stiffness of a surgical construct. Such mechanical data may influence construct design in primary and revision surgeries of the cervical spine and cervicothoracic junction.

Food Allergy Testing.

Although the gold standard for diagnosis of immunoglobulin E (IgE)-mediated food allergy is an oral food challenge, clinically relevant biomarkers of IgE sensitization, including serum-specific IgE and skin prick testing, can aid in diagnosis. Clinically useful values have been defined for individual foods. More recently, specific IgE to particular protein components has provided additional diagnostic value. In summary, food allergy diagnostics to evaluate IgE sensitization are clinically useful and continue to evolve to improve evaluation of IgE-mediated food allergies.

FUNCTIONAL PRINCIPAL VARIANCE COMPONENT TESTING FOR A GENETIC ASSOCIATION STUDY OF HIV PROGRESSION.

HIV-1C is the most prevalent subtype of HIV-1 and accounts for over half of HIV-1 infections worldwide. Host genetic influence of HIV infection has been previously studied in HIV-1B, but little attention has been paid to the more prevalent subtype C. To understand the role of host genetics in HIV-1C disease progression, we perform a study to assess the association between longitudinally collected measures of disease and more than 100,000 genetic markers located on chromosome 6. The most common approach to analyzing longitudinal data in this context is linear mixed effects models, which may be overly simplistic in this case. On the other hand, existing flexible and nonparametric methods either require densely sampled points, restrict attention to a single SNP, lack testing procedures, or are cumbersome to fit on the genome-wide scale. We propose a functional principal variance component (FPVC) testing framework which captures the nonlinearity in the CD4 and viral load with low degrees of freedom and is fast enough to carry out thousands or millions of times. The FPVC testing unfolds in two stages. In the first stage, we summarize the markers of disease progression according to their major patterns of variation via functional principal components analysis (FPCA). In the second stage, we employ a simple working model and variance component testing to examine the association between the summaries of disease progression and a set of single nucleotide polymorphisms. We supplement this analysis with simulation results which indicate that FPVC testing can offer large power gains over the standard linear mixed effects model.

Diagnosis of Food Allergy.

The prevalence of food allergies has been on the increase over the last 2 decades. Diagnosing food allergies can be complicated, as there are multiple types that have distinct clinical and immunologic features. Food allergies are broadly classified into immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed food allergic reactions. This review focuses on the clinical manifestations of the different categories of food allergies and the different tests available to guide the clinician toward an accurate diagnosis.

Diagnosis and management of food allergies: new and emerging options: a systematic review.

It is reported that 6% of children and 3% of adults have food allergies, with studies suggesting increased prevalence worldwide over the last few decades. Despite this, our diagnostic capabilities and techniques for managing patients with food allergies remain limited. We have conducted a systematic review of literature published within the last 5 years on the diagnosis and management of food allergies. While the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge, this assessment is resource intensive and impractical in most clinical situations. In an effort to reduce the need for the double-blind, placebo-controlled food challenge, several risk-stratifying tests are employed, namely skin prick testing, measurement of serum-specific immunoglobulin E levels, component testing, and open food challenges. Management of food allergies typically involves allergen avoidance and carrying an epinephrine autoinjector. Clinical research trials of oral immunotherapy for some foods, including peanut, milk, egg, and peach, are under way. While oral immunotherapy is promising, its readiness for clinical application is controversial. In this review, we assess the latest studies published on the above diagnostic and management modalities, as well as novel strategies in the diagnosis and management of food allergy.