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BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).
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Antialérgicos , Desensibilización Inmunológica , Hipersensibilidad a los Alimentos , Omalizumab , Adolescente , Niño , Humanos , Lactante , Alérgenos/efectos adversos , Arachis/efectos adversos , Desensibilización Inmunológica/métodos , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/terapia , Omalizumab/efectos adversos , Omalizumab/uso terapéutico , Hipersensibilidad al Cacahuete/tratamiento farmacológico , Hipersensibilidad al Cacahuete/inmunología , Hipersensibilidad al Cacahuete/terapia , Antialérgicos/administración & dosificación , Antialérgicos/uso terapéutico , Preescolar , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.
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Vacuna BNT162 , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , SARS-CoV-2 , Humanos , Persona de Mediana Edad , Masculino , Adulto , Femenino , Método Doble Ciego , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Anciano , Adolescente , Adulto Joven , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Recurrencia , Vacunación , Vacuna nCoV-2019 mRNA-1273 , Estudios CruzadosRESUMEN
BACKGROUND: While food allergy (FA) can be fatal, the greatest public health impact of FA arguably lies in its detrimental effect on quality of life (FAQOL). Understanding the factors that contribute to FAQOL at different ages is essential to develop personalized interventions that will improve FAQOL. OBJECTIVE: To determine the most influential factors that impact FAQOL across ages in well-phenotyped participants with confirmed FA. METHODS: One hundred and twenty-five individuals aged 2-28 years with IgE-mediated FA completed validated age-specific FAQOL questionnaires. The relationship between demographic/clinical variables and scores were analyzed to identify key predictors of FAQOL. RESULTS: Poor FAQOL was associated with increasing age, strict avoidance practices, reactions to trace exposures, and more severe reactions as assessed by epinephrine use, anaphylaxis, and/or treatment in the emergency department; FAQOL improved with time from the event. FAQOL was worse in subjects avoiding >2 versus ≤2 foods and in those avoiding milk, egg, soy, sesame, or wheat. Number of foods avoided had greatest impact on children ages 2-7 years, while total number of allergic reactions strongly impacted FAQOL in teens and adults; FAQOL of subjects ages 8-12 years appeared less affected by these variables compared to other age groups. A decision tree analysis identified key predictors of overall FAQOL (age, number of food avoidances, and time since epinephrine use) that can be used to guide intervention strategies to improve FAQOL. CONCLUSION: We directly compared FAQOL in extensively phenotyped children, teenagers, and adults with confirmed IgE-mediated FA. Age; timing, number, and severity of reactions; type and number of FA; and food avoidance practices influence FAQOL and should guide intervention strategies.
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BACKGROUND: Peanut allergy affects 1% to 2% of European children. Early introduction of peanut into the diet reduces allergy in high-risk infants. OBJECTIVE: We aimed to determine the optimal target populations and timing of introduction of peanut products to prevent peanut allergy in the general population. METHODS: Data from the Enquiring About Tolerance (EAT; n = 1303; normal risk; 3-year follow-up; ISRCTN14254740) and Learning Early About Peanut Allergy study (LEAP; n = 640; high risk; 5-year follow-up; NCT00329784) randomized controlled trials plus the Peanut Allergy Sensitization (PAS; n = 194; low and very high risk; 5-year follow-up) observational study were used to model the intervention in a general population. Peanut allergy was defined by blinded peanut challenge or diagnostic skin prick test result. RESULTS: Targeting only the highest-risk infants with severe eczema reduced the population disease burden by only 4.6%. Greatest reductions in peanut allergy were seen when the intervention was targeted only to the larger but lower-risk groups. A 77% reduction in peanut allergy was estimated when peanut was introduced to the diet of all infants, at 4 months with eczema, and at 6 months without eczema. The estimated reduction in peanut allergy diminished with every month of delayed introduction. If introduction was delayed to 12 months, peanut allergy was only reduced by 33%. CONCLUSIONS: The preventive benefit of early introduction of peanut products into the diet decreases as age at introduction increases. In countries where peanut allergy is a public health concern, health care professionals should help parents introduce peanut products into their infants' diet at 4 to 6 months of life.
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Eccema , Hipersensibilidad al Cacahuete , Lactante , Niño , Humanos , Hipersensibilidad al Cacahuete/epidemiología , Hipersensibilidad al Cacahuete/prevención & control , Hipersensibilidad al Cacahuete/diagnóstico , Riesgo , Dieta , Arachis , Alérgenos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Acute increases of ≥20% + 2 ng/mL (20 + 2 rule) over basal serum tryptase (BST) is the recommended threshold supporting a clinical diagnosis of anaphylaxis. Prospective studies have demonstrated high sensitivity for this algorithm after parenteral exposure, but specificity has not been evaluated. OBJECTIVE: We sought to define a serum tryptase change that distinguishes baseline variability from anaphylaxis on the basis of intraindividual variation in BST. METHODS: Ninety-three total subjects with atopy (n = 62) or hereditary α-tryptasemia (HαT) (n = 31) and ≥2 BST measurements were identified. Sequential BST variability measurements were modeled and threshold ratios that optimized sensitivity and/or specificity determined. Models were tested in 22 individuals with physician-diagnosed anaphylaxis and validated in independent cohorts of individuals with HαT (n = 33), indolent systemic mastocytosis (ISM) (n = 52), and ISM + HαT (n = 12). Mature tryptase levels were measured in HαT (n = 19) and ISM (n = 20). An online application was developed for clinical use. RESULTS: As a result of BST variability, 9.7% (9/93) of primary cohort patients, and 18% (6/33) of HαT, 30% (16/53) of ISM, and 25% (3/12) of ISM + HαT patients from validation cohorts met the 20 + 2 rule despite absent immediate hypersensitivity symptoms; mature tryptase was noncontributory among individuals with HαT or ISM at baseline. A ratio of acute tryptase/BST exceeding 1.685 provided the optimized diagnostic rule for jointly maximizing sensitivity and specificity. Statistically significant improvement in specificity relative to the 20 + 2 rule was observed among individuals with elevated BST caused by HαT and ISM. CONCLUSIONS: Using an acute tryptase/BST ratio of 1.685 improves specificity of measured changes among individuals with HαT and ISM while maintaining high sensitivity for confirmation of anaphylaxis.
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Anafilaxia , Mastocitosis Sistémica , Mastocitosis , Anafilaxia/diagnóstico , Humanos , Mastocitos , Estudios Prospectivos , TriptasasRESUMEN
PURPOSE: Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone. METHODS: We defined the bone phenotype and clinical predictors of low bone density and fracture risk in 77 patients with LDS type 1 to type 5. RESULTS: Patients with LDS had dual-energy x-ray absorptiometry (DXA) Z-scores significantly < 0, and 50% of children and 9% of adults had Z-scores < -2. Sixty percent of patients had ≥1 fracture, and 24% of patients with spinal x-rays scans showed spinal compression fractures. Lower body mass index, asthma, male sex and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. The count of 5 LDS-associated skeletal features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly) in patients with LDS was correlated with DXA Z-score. Adults with ≥1 skeletal features had DXA Z-scores significantly < 0, and children with >2 features had DXA Z-score significantly < -2. Bone turnover markers suggest accelerated bone resorption. Data from 5 patients treated with bisphosphonates suggest a beneficial effect. CONCLUSION: All LDS types are associated with reduced bone density and increased risk of fracture, which may be due to increased bone resorption. Clinical features can predict a subgroup of patients at highest risk of low bone density and fracture risk.
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Enfermedades Óseas Metabólicas , Fracturas Óseas , Síndrome de Loeys-Dietz , Absorciometría de Fotón , Densidad Ósea , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/epidemiología , Humanos , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/genética , MasculinoRESUMEN
BACKGROUND: Idiopathic anaphylaxis (IA) is a diagnosis of exclusion, thus taking away the option of therapeutic management focused on eliminating the inciting agent. Epinephrine and antihistamines followed by systemic corticosteroids are the mainstays of therapy for acute events. There is no prophylactic therapy that reliably prevents anaphylaxis. OBJECTIVE: We sought to determine the efficacy of omalizumab in the management of patients with frequent episodes of IA in a double-blind, placebo-controlled trial. METHODS: We prospectively enrolled 19 patients with frequent IA (≥6 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, mutational analysis for KIT D816V, and bone marrow evaluation to rule out a clonal mast cell disorder. Computer-generated random numbers were provided by the study pharmacist. The primary end point was anaphylactic events in the 6 months after baseline. Sixteen patients completed the primary trial. RESULTS: No statistically significant difference was demonstrated between the placebo and treated groups. There was a trend for efficacy in the treatment group, particularly after 60 days. Overall, the safety profile was favorable without long-term side effects. CONCLUSIONS: Omalizumab was safely administered to a difficult-to-treat patient population with IA. The efficacy results trended modestly in favor of the treatment group, but no statistically significant differences were detected.
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Anafilaxia/prevención & control , Antialérgicos/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Omalizumab/uso terapéutico , Adolescente , Adulto , Anciano , Anafilaxia/etiología , Método Doble Ciego , Femenino , Humanos , Hipersensibilidad/complicaciones , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Masculino , Persona de Mediana Edad , Efecto Placebo , Adulto JovenRESUMEN
STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4(+) and CD8(+) T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors BCL6 and SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses.
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Memoria Inmunológica/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Adolescente , Adulto , Apoptosis/genética , Apoptosis/inmunología , Secuencia de Bases , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica , Herpesvirus Humano 3/inmunología , Humanos , Síndrome de Job/genética , Síndrome de Job/inmunología , Síndrome de Job/virología , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Linfocitos T/metabolismo , Adulto JovenRESUMEN
Multiple comparison adjustments have a long history, yet confusion remains about which procedures control type 1 error rate in a strong sense and how to show this. Part of the confusion stems from a powerful technique called the closed testing principle, whose statement is deceptively simple, but is sometimes misinterpreted. This primer presents a straightforward way to think about multiplicity adjustment.
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The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the use and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: (1) propose a study design to compare the effectiveness and safety of subcutaneous versus sublingual AAIT; (2) propose a study design to compare the effectiveness and safety of AAIT by using 1 or a few allergens versus all or most allergens to which a patient is sensitized; (3) propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; and (4) propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop, and revised for this report. The proposed trials would be of long duration and require large highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease.
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Asma/terapia , Desensibilización Inmunológica/métodos , Hipersensibilidad/terapia , Administración Sublingual , Contaminantes Atmosféricos/inmunología , Alérgenos/inmunología , Asma/inmunología , Ensayos Clínicos como Asunto , Consensus Development Conferences, NIH as Topic , Educación , Testimonio de Experto , Humanos , Hipersensibilidad/inmunología , Inyecciones Subcutáneas , National Institute of Allergy and Infectious Diseases (U.S.) , Proyectos de Investigación , Estados UnidosRESUMEN
BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.
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Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Guanilato Ciclasa/genética , Guanilato Ciclasa/inmunología , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Adulto , Femenino , Humanos , Masculino , Mutación , FenotipoRESUMEN
This paper introduces a test of superiority of new anti-infective drug B over comparator drug A based on a randomized clinical trial. This test can be used to demonstrate assay (trial) sensitivity for noninferiority trials and rigorously tailor drug choice for individual patients. Our approach uses specialized baseline covariates XA ,XB , which should predict the benefits of drug A and drug B, respectively. Using a response surface model for the treatment effect, we test for superiority at the (XA ,XB ) point that is most likely to show superiority. We identify this point based on estimates from a novel half-blind pseudo likelihood, where we augment a blinded likelihood (mixed over the treatment indicator) with likelihoods for the overall success rates for drug A and drug B (mixed over XA ,XB ). The augmentation results in much better estimates than those based on the mixed blinded likelihood alone but, interestingly, the estimates almost behave as if they were based on fully blinded data. We also develop an analogous univariate method using XA for settings where XB has little variation. Permutation methods are used for testing. If the "half-blind" test rejects, pointwise confidence interval can be used to identify patients who would benefit from drug B. We compare the new tests to other methods with an example and via simulations.
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Antiinfecciosos/uso terapéutico , Estudios de Equivalencia como Asunto , Método Simple Ciego , Interpretación Estadística de Datos , Humanos , Funciones de Verosimilitud , Modelos EstadísticosRESUMEN
BACKGROUND: Diagnosing food allergy in patients with atopic dermatitis (AD) is complicated by their high rate of asymptomatic sensitization to foods, which can lead to misdiagnosis and unnecessary food avoidance. OBJECTIVE: We sought to determine whether food-specific (sIgE) or component immunoglobulin (Ig) E levels could predict allergic status in patients with moderate to severe AD and elevated total IgE. METHODS: Seventy-eight children (median age, 10.7 years) with moderate to severe AD were assessed for a history of clinical reactivity to milk, egg, peanut, wheat, and soy. The IgE levels for each food and its components were determined by ImmunoCAP. The level and pattern of IgE reactivity to each food and its components, and their ratio to total IgE, were compared between subjects who were allergic and tolerant to each food. RESULTS: Ninety-one percent of subjects were sensitized, and 51% reported allergic reactivity to at least 1 of the 5 most common food allergens. Allergy to milk, egg, and peanut were most common, and IgE levels to each of these foods were significantly higher in the allergic group. Component IgEs most associated with milk, egg, and peanut allergy were Bos d8, Gal d1, and Ara h2, respectively. The ratio of sIgE to total IgE offered no advantage to sIgE alone in predicting allergy. CONCLUSION: Specific IgE levels and the pattern of IgE reactivity to food components can distinguish AD subjects allergic vs tolerant to the major food allergens and may therefore be helpful in guiding the clinical management of these patients.
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Dermatitis Atópica/diagnóstico , Hipersensibilidad a los Alimentos/diagnóstico , Inmunoglobulina E/sangre , Adolescente , Adulto , Animales , Arachis/efectos adversos , Niño , Preescolar , Dermatitis Atópica/sangre , Dermatitis Atópica/inmunología , Huevos/efectos adversos , Femenino , Hipersensibilidad a los Alimentos/sangre , Hipersensibilidad a los Alimentos/inmunología , Humanos , Masculino , Leche/efectos adversos , Índice de Severidad de la Enfermedad , Adulto JovenAsunto(s)
Hipersensibilidad a los Alimentos , Inmunoglobulina E , Niño , Humanos , Lactante , Densidad Ósea , AlérgenosRESUMEN
Although the P value from a Wilcoxon-Mann-Whitney test is used often with randomized experiments, it is rarely accompanied with a causal effect estimate and its confidence interval. The natural parameter for the Wilcoxon-Mann-Whitney test is the Mann-Whitney parameter, Ï, which measures the probability that a randomly selected individual in the treatment arm will have a larger response than a randomly selected individual in the control arm (plus an adjustment for ties). We show that the Mann-Whitney parameter may be framed as a causal parameter and show that it is not equal to a closely related and nonidentifiable causal effect, ψ, the probability that a randomly selected individual will have a larger response under treatment than under control (plus an adjustment for ties). We review the paradox, first expressed by Hand, that the ψ parameter may imply that the treatment is worse (or better) than control, while the Mann-Whitney parameter shows the opposite. Unlike the Mann-Whitney parameter, ψ is nonidentifiable from a randomized experiment. We review some nonparametric assumptions that rule out Hand's paradox through bounds on ψ and use bootstrap methods to make inferences on those bounds. We explore the relationship of the proportional odds parameter to Hand's paradox, showing that the paradox may occur for proportional odds parameters between 1/9 and 9. Thus, large effects are needed to ensure that if treatment appears better by the Mann-Whitney parameter, then treatment improves responses in most individuals. We demonstrate these issues using a vaccine trial.
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Ensayos Clínicos Controlados Aleatorios como Asunto , Estadísticas no Paramétricas , Simulación por Computador , Intervalos de Confianza , Humanos , Vacunas contra la Malaria/administración & dosificación , Modelos Estadísticos , ProbabilidadRESUMEN
BACKGROUND: In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected. OBJECTIVE: We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab. METHODS: Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4+ regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy. RESULTS: Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab- but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions. CONCLUSIONS: Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab.
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Antialérgicos/uso terapéutico , Basófilos/inmunología , Desensibilización Inmunológica/métodos , Hipersensibilidad a la Leche/terapia , Omalizumab/uso terapéutico , Linfocitos T Reguladores/inmunología , Administración Oral , Adolescente , Adulto , Alérgenos/inmunología , Caseínas/inmunología , Proliferación Celular , Niño , Ensayos Clínicos como Asunto , Terapia Combinada , Femenino , Histamina/metabolismo , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Activación de Linfocitos , Masculino , Hipersensibilidad a la Leche/inmunología , Tetraspanina 30 , Adulto JovenRESUMEN
We review and develop pointwise confidence intervals for a survival distribution with right-censored data for small samples, assuming only independence of censoring and survival. When there is no censoring, at each fixed time point, the problem reduces to making inferences about a binomial parameter. In this case, the recently developed beta product confidence procedure (BPCP) gives the standard exact central binomial confidence intervals of Clopper and Pearson. Additionally, the BPCP has been shown to be exact (gives guaranteed coverage at the nominal level) for progressive type II censoring and has been shown by simulation to be exact for general independent right censoring. In this paper, we modify the BPCP to create a 'mid-p' version, which reduces to the mid-p confidence interval for a binomial parameter when there is no censoring. We perform extensive simulations on both the standard and mid-p BPCP using a method of moments implementation that enforces monotonicity over time. All simulated scenarios suggest that the standard BPCP is exact. The mid-p BPCP, like other mid-p confidence intervals, has simulated coverage closer to the nominal level but may not be exact for all survival times, especially in very low censoring scenarios. In contrast, the two asymptotically-based approximations have lower than nominal coverage in many scenarios. This poor coverage is due to the extreme inflation of the lower error rates, although the upper limits are very conservative. Both the standard and the mid-p BPCP methods are available in our bpcp R package. Published 2016. This article is US Government work and is in the public domain in the USA.
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Intervalos de Confianza , Análisis de Supervivencia , HumanosRESUMEN
BACKGROUND: The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication. OBJECTIVE: We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management. METHODS: Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology. RESULTS: In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). CONCLUSIONS: The majority of children experienced major or complete disease resolution (57%), whereas the remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.
Asunto(s)
Médula Ósea/patología , Mastocitosis Cutánea , Mastocitosis Sistémica , Triptasas/sangre , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina E/sangre , Lactante , Masculino , Mastocitos/inmunología , Mastocitosis Cutánea/sangre , Mastocitosis Cutánea/diagnóstico por imagen , Mastocitosis Cutánea/inmunología , Mastocitosis Cutánea/patología , Mastocitosis Sistémica/sangre , Mastocitosis Sistémica/diagnóstico por imagen , Mastocitosis Sistémica/inmunología , Mastocitosis Sistémica/patología , Pronóstico , Ultrasonografía , Adulto JovenRESUMEN
We present a simple general method for combining two one-sample confidence procedures to obtain inferences in the two-sample problem. Some applications give striking connections to established methods; for example, combining exact binomial confidence procedures gives new confidence intervals on the difference or ratio of proportions that match inferences using Fisher's exact test, and numeric studies show the associated confidence intervals bound the type I error rate. Combining exact one-sample Poisson confidence procedures recreates standard confidence intervals on the ratio, and introduces new ones for the difference. Combining confidence procedures associated with one-sample t-tests recreates the Behrens-Fisher intervals. Other applications provide new confidence intervals with fewer assumptions than previously needed. For example, the method creates new confidence intervals on the difference in medians that do not require shift and continuity assumptions. We create a new confidence interval for the difference between two survival distributions at a fixed time point when there is independent censoring by combining the recently developed beta product confidence procedure for each single sample. The resulting interval is designed to guarantee coverage regardless of sample size or censoring distribution, and produces equivalent inferences to Fisher's exact test when there is no censoring. We show theoretically that when combining intervals asymptotically equivalent to normal intervals, our method has asymptotically accurate coverage. Importantly, all situations studied suggest guaranteed nominal coverage for our new interval whenever the original confidence procedures themselves guarantee coverage.
Asunto(s)
Algoritmos , Biometría/métodos , Interpretación Estadística de Datos , Modelos Estadísticos , Simulación por Computador , Intervalos de Confianza , Métodos Epidemiológicos , Análisis Numérico Asistido por Computador , Tamaño de la Muestra , Distribuciones EstadísticasRESUMEN
We propose a beta product confidence procedure (BPCP) that is a non-parametric confidence procedure for the survival curve at a fixed time for right-censored data assuming independent censoring. In such situations, the Kaplan-Meier estimator is typically used with an asymptotic confidence interval (CI) that can have coverage problems when the number of observed failures is not large, and/or when testing the latter parts of the curve where there are few remaining subjects at risk. The BPCP guarantees central coverage (i.e. ensures that both one-sided error rates are no more than half of the total nominal rate) when there is no censoring (in which case it reduces to the Clopper-Pearson interval) or when there is progressive type II censoring (i.e. when censoring only occurs immediately after failures on fixed proportions of the remaining individuals). For general independent censoring, simulations show that the BPCP maintains central coverage in many situations where competing methods can have very substantial error rate inflation for the lower limit. The BPCP gives asymptotically correct coverage and is asymptotically equivalent to the CI on the Kaplan-Meier estimator using Greenwood's variance. The BPCP may be inverted to create confidence procedures for a quantile of the underlying survival distribution. Because the BPCP is easy to implement, offers protection in settings when other methods fail, and essentially matches other methods when they succeed, it should be the method of choice.