Home Endotoxin Exposure and Wheeze in Infants: Correction for Bias Due to Exposure Measurement Error

Exposure to elevated levels of endotoxin in family-room dust was previously observed to be significantly associated with increased wheeze in the first year of life among a cohort of 404 children in the Boston, Massachusetts, metropolitan area. However, it is likely that family-room dust endotoxin was a surrogate for airborne endotoxin exposure. Therefore, a related substudy characterized the relationship between levels of airborne household endotoxin and the level of endotoxin present in house dust, in addition to identifying other significant predictors of airborne endotoxin in the home. We now reexamine the relationship between endotoxin exposure and wheeze under the assumption that the level of airborne endotoxin in the home is the exposure of interest and that the amount of endotoxin in household dust is a surrogate for this exposure. We applied a measurement error correction technique, using all available data to estimate the effect of endotoxin exposure in terms of airborne concentration and accounting for the measurement error induced by using house-dust endotoxin as a surrogate measure in the portion of the data in which airborne endotoxin could not be directly measured. After adjusting for confounding by lower respiratory infection status and race/ethnicity, endotoxin exposure was found to be significantly associated with a nearly 6-fold increase in prevalence of wheeze for a one interquartile range increase in airborne endotoxin (95% confidence interval, 1.2–26) among the 360 children in households with dust endotoxin levels between the 5th and 95th percentiles

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia

Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824

Exploring the efficacy of an electronic symptom assessment and self-care intervention to preserve physical function in individuals receiving neurotoxic chemotherapy

Abstract Background Impaired physical function due to chemotherapy-induced peripheral neuropathy (CIPN) symptoms may lead to diminished quality of life. However, even with the knowledge of the effects of CIPN on physical function, clinicians infrequently assess and manage CIPN. Interventions that prioritize the early identification of CIPN to provide prompt treatment may reduce the impact of CIPN on physical function. The purpose of this paper is to compare self-reported physical function in individuals receiving neurotoxic chemotherapy between Electronic Symptom Assessment-Cancer (ESRA-C) intervention group (e.g., opportunity for symptom screening, self-care recommendations, communication coaching, and symptom tracking) and control group participants (i.e., electronic assessment alone). Secondary outcomes include pain intensity, sensory/motor CIPN, depression, fatigue, and insomnia. Methods The data used in this paper are a subset of a randomized controlled trial that examined the impact of the ESRA-C intervention on symptom distress in individuals receiving cancer treatment. Since the interest in this analysis is on the effects of neurotoxic chemotherapy on physical function, subjects were included if they received platinum and/or taxane-based chemotherapy and completed the baseline and end-of-treatment measures. Participants completed standardized questionnaires of physical function, CIPN, fatigue, depression, pain intensity, and insomnia prior to treatment, 3–6 weeks after treatment initiation, and after the completion of treatment. Changes in mean scores are compared between groups using linear mixed models adjusting for age. Results Intervention group participants reported significantly less reduction in physical functioning (baseline: 87.4/100; end-of-treatment: 84.5/100) relative to the control (baseline: 90.2/100; end-of-treatment: 81.8/100) (p = 0.011). For secondary measures, significantly less depression (p = 0.005) was observed in the intervention group as compared to the control, but otherwise, there were no between-group differences. Among participants who received high cumulative doses of neurotoxic chemotherapy, the intervention group reported significantly less severe sensory (p = 0.007) and motor CIPN (p = 0.039) relative to the control. Conclusion Use of the ESRA-C intervention led to less reduction in physical function in comparison to the control in individuals receiving neurotoxic chemotherapy. Further research is needed to confirm our findings and to identify how electronic symptom assessment technology may mediate physical function preservation. Trial registration ClinicalTrials.Gov NCT00852852. Registered 27 February 2009

Imputation methods for missing failure times in recurrent-event survival analysis: Application to suicide attempts in the transgender population.

Suicide risk among transgender populations is an important public health issue. In a project evaluating association between gender affirmation and suicide attempts in the US Transgender Survey, we evaluated the relationship between gender affirmation and risk for suicide attempts. One of the challenges is that the age at suicide attempts was only collected for the first and last attempt. The initial zero-inflated negative binomial model enabled us to evaluate the association between gender affirmation and number of suicide attempts per 5 years adjusting for other covariates. However, ignoring missing failure times of recurrent events may have caused bias and loss of efficiency. In this paper, we use a recurrent-event survival analysis incorporating time-varying covariates with three approaches to impute the age at suicide attempt, estimates from three imputation approaches are similar. We were able to confirm the findings from the initial model and identify additional associations that were not detected in the initial analysis. Findings suggest the need to consider additional analytical approaches in settings with high data missingness by design. Research to validate and compare measures that ask first and last attempt to those which enumerate all attempts in this population will be important for future surveys

Imputation methods for missing failure times in recurrent-event survival analysis: Application to suicide attempts in the transgender population

Suicide risk among transgender populations is an important public health issue. In a project evaluating association between gender affirmation and suicide attempts in the US Transgender Survey, we evaluated the relationship between gender affirmation and risk for suicide attempts. One of the challenges is that the age at suicide attempts was only collected for the first and last attempt. The initial zero-inflated negative binomial model enabled us to evaluate the association between gender affirmation and number of suicide attempts per 5 years adjusting for other covariates. However, ignoring missing failure times of recurrent events may have caused bias and loss of efficiency. In this paper, we use a recurrent-event survival analysis incorporating time-varying covariates with three approaches to impute the age at suicide attempt, estimates from three imputation approaches are similar. We were able to confirm the findings from the initial model and identify additional associations that were not detected in the initial analysis. Findings suggest the need to consider additional analytical approaches in settings with high data missingness by design. Research to validate and compare measures that ask first and last attempt to those which enumerate all attempts in this population will be important for future surveys

Fig 2 -

Histogram of original data (2A) and 10 datasets generated from three imputation approaches. SRI-uniform (2B, assumes attempts randomly occurred following a uniform distribution), SRI-probability (2C, assumes probabilities of the observed values of age at attempt used to generate the missing data) and MI (2D, multiple imputation regression model).</p

Unadjusted hazard ratios of gender affirmation in binary gender identity group compared among imputation methods with 100 imputation datasets.

Reference group = no gender affirmation of any type. Social (No surgery/hormones) = participants had social affirmation but did not have surgery or hormones. Social (Surgery or hormones) = participants had social affirmation and either or both of surgery and hormones. (DOCX)</p

Fig 1 -

Two hypothetical participants showing complete information on exposures and events (a) and missing time of event (b). (a) Timeline example 1; (b) Timeline example 2.</p