Emulating a gravity model to infer the spatiotemporal dynamics of an infectious disease

Probabilistic models for infectious disease dynamics are useful for understanding the mechanism underlying the spread of infection. When the likelihood function for these models is expensive to evaluate, traditional likelihood-based inference may be computationally intractable. Furthermore, traditional inference may lead to poor parameter estimates and the fitted model may not capture important biological characteristics of the observed data. We propose a novel approach for resolving these issues that is inspired by recent work in emulation and calibration for complex computer models. Our motivating example is the gravity time series susceptible-infected-recovered (TSIR) model. Our approach focuses on the characteristics of the process that are of scientific interest. We find a Gaussian process approximation to the gravity model using key summary statistics obtained from model simulations. We demonstrate via simulated examples that the new approach is computationally expedient, provides accurate parameter inference, and results in a good model fit. We apply our method to analyze measles outbreaks in England and Wales in two periods, the pre-vaccination period from 1944-1965 and the vaccination period from 1966-1994. Based on our results, we are able to obtain important scientific insights about the transmission of measles. In general, our method is applicable to problems where traditional likelihood-based inference is computationally intractable or produces a poor model fit. It is also an alternative to approximate Bayesian computation (ABC) when simulations from the model are expensive.Comment: 31 pages, 8 figures and 2 table

Phase 1 doseâ finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/1/cncr32539.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153201/2/cncr32539_am.pd

Assessing the Relationship between Gestational Glycemic Control and Risk of Preterm Birth in Women with Type 1 Diabetes: A Joint Modeling Approach

Background. Characterizing maternal glucose sampling over the course of the entire pregnancy is an important step toward improvement in prediction of adverse birth outcome, such as preterm birth, for women with type 1 diabetes mellitus (T1DM). Objectives. To characterize the relationship between the gestational glycemic profile and risk of preterm birth using a joint modeling approach. Methods. A joint model was developed to simultaneously characterize the relationship between a longitudinal outcome (daily blood glucose sampling) and an event process (preterm birth). A linear mixed effects model using natural cubic splines was fitted to predict the longitudinal submodel. Covariates included mother’s age at last menstrual period, age at diabetes onset, body mass index, hypertension, retinopathy, and nephropathy. Various association structures (value, value plus slope, and area under the curve) were examined before selecting the final joint model. We compared the joint modeling approach to the time-dependent Cox model (TDCM). Results. A total of 16,480 glucose readings over gestation (range: 50-260 days) with 32 women (28%) having preterm birth was included in the study. Mother’s age at last menstrual period and age at diabetes onset were statistically significant (beta = 1.29, 95% CI 1.10, 1.72; beta = 0.84, 95% CI 0.62, 0.98) for the longitudinal submodel, reflecting that older women tended to have higher mean blood glucose and those with later diabetes onset tended to have a lower mean blood glucose level. The presence of nephropathy was statistically significant in the event submodel (beta = 2.29, 95% CI 1.05, 4.48). Cumulative association parameterization provided the best joint model fit. The joint model provided better fit compared to the time-dependent Cox model (DIC JM=19,895; DIC TDCM=19,932). Conclusion. The joint model approach was able to simultaneously characterize the glycemic profile and assess the risk of preterm birth and provided additional insights and a better model fit compared to the time-dependent Cox model

Hand Nicotine and Cotinine In Children Exposed to Cigars: A Pilot Study.

ObjectivesPast research has not examined secondhand and thirdhand smoke (THS) exposure in children of cigar smokers. We examined hand nicotine and cotinine levels in children of cigar smokers to explore the contribution of cigar smoke to tobacco smoke exposure (TSE).MethodsParticipants were children (N = 24; mean (SD) age = 6.5 (3.6) years) whose parents smoked cigars only or poly-used cigars and/or cigarettes. Primary outcomes were hand nicotine and urinary cotinine levels.ResultsAll children had detectable hand nicotine (range: 7.6-312.5ng/wipe) and cotinine (range: 0.3-100.3ng/ml). Positive correlations were found between hand nicotine and cotinine (r = 0.693, p = .001), hand nicotine and parents who also smoked cigarettes (r = 0.407, p = .048), and hand nicotine and number of smokers around the child (r = 0.436, p = .03). Hand nicotine (r = -0.464, p = .02), but not cotinine (r = -0.266, p = .26), was negatively correlated with child age. Multiple regression results indicated a positive association between hand nicotine and cotinine (p = .002; semi-partial r2 = 0.415), irrespective of child age.ConclusionsThe significant association of hand nicotine with urinary cotinine suggests that THS pollution should be assessed in evaluating children's overall TSE to cigars and other tobacco products, and hand nicotine may be a proxy for overall TSE. Younger children may have increased THS pollutant uptake

Predicting Daily Urban Fine Particulate Matter Concentrations Using a Random Forest Model

The short-term and acute health effects of fine particulate matter less than 2.5 μm (PM_2.5) have highlighted the need for exposure assessment models with high spatiotemporal resolution. Here, we utilize satellite, meteorologic, atmospheric, and land-use data to train a random forest model capable of accurately predicting daily PM_2.5 concentrations at a resolution of 1 × 1 km throughout an urban area encompassing seven counties. Unlike previous models based on aerosol optical density (AOD), we show that the missingness of AOD is an effective predictor of ground-level PM_2.5 and create an ensemble model that explicitly deals with AOD missingness and is capable of predicting with complete spatial and temporal coverage of the study domain. Our model performed well with an overall cross-validated root mean squared error (RMSE) of 2.22 μg/m³ and a cross-validated <i>R</i>² of 0.91. We illustrate the daily changing spatial patterns of PM_2.5 concentrations across our urban study area made possible by our accurate, high-resolution model. The model will facilitate high-resolution assessment of both long-term and acute PM_2.5 exposures in order to quantify their associations with related health outcomes

The Associations of <i>Trans</i>-3′-Hydroxy Cotinine, Cotinine, and the Nicotine Metabolite Ratio in Pediatric Patients with Tobacco Smoke Exposure

(1) Background: Trans-3′-hydroxy cotinine (3HC) and cotinine (COT) are tobacco smoke exposure (TSE) biomarkers and the 3HC/COT ratio is a marker of CYP2A6 activity, an enzyme which metabolizes nicotine. The primary objective was to assess the associations of these TSE biomarkers with sociodemographics and TSE patterns in children who lived with ≥1 smoker. (2) Methods: A convenience sample of 288 children (mean age (SD) = 6.42 (4.8) years) was recruited. Multiple linear regression models were built to assess associations of sociodemographics and TSE patterns with urinary biomarker response variables: (1) 3HC, (2) COT, (3) 3HC+COT sum, and (4) 3HC/COT ratio. (3) Results: All children had detectable 3HC (Geometric Mean [GeoM] = 32.03 ng/mL, 95%CI = 26.97, 38.04) and COT (GeoM = 10.24 ng/mL, 95%CI = 8.82, 11.89). Children with higher cumulative TSE had higher 3HC and COT (β^ = 0.03, 95%CI = 0.01, 0.06, p = 0.015 and β^ = 0.03, 95%CI = 0.01, 0.05, p = 0.013, respectively). Highest 3HC+COT sum levels were in children who were Black (β^ = 0.60, 95%CI = 0.04, 1.17, p = 0.039) and who had higher cumulative TSE (β^ = 0.03, 95%CI = 0.01, 0.06, p = 0.015). Lowest 3HC/COT ratios were in children who were Black (β^ = −0.42, 95%CI = −0.78, −0.07, p = 0.021) and female (β^ = −0.32, 95%CI = −0.62, −0.01, p = 0.044). (4) Conclusion: Results indicate that there are racial and age-related differences in TSE, most likely due to slower nicotine metabolism in non-Hispanic Black children and in younger children

A Joint Model for Unbalanced Nested Repeated Measures with Informative Drop-Out Applied to Ambulatory Blood Pressure Monitoring Data

This study proposes a Bayesian joint model with extended random effects structure that incorporates nested repeated measures and provides simultaneous inference on treatment effects over time and drop-out patterns. The proposed model includes flexible splines to characterize the circadian variation inherent in blood pressure sequences, and we assess the effectiveness of an intervention to resolve pediatric obstructive sleep apnea. We demonstrate that the proposed model and its conventional two-stage counterpart provide similar estimates of nighttime blood pressure but estimates on the mean evolution of daytime blood pressure are discrepant. Our simulation studies tailored to the motivating data suggest reasonable estimation and coverage probabilities for both fixed and random effects. Computational challenges of model implementation are discussed

Differential associations of hand nicotine and urinary cotinine with children's exposure to tobacco smoke and clinical outcomes.

BackgroundChildren's overall tobacco smoke exposure (TSE) consists of both inhalation of secondhand smoke (SHS) and ingestion, dermal uptake, and inhalation of thirdhand smoke (THS) residue from dust and surfaces in their environments.ObjectivesOur objective was to compare the different roles of urinary cotinine as a biomarker of recent overall TSE and hand nicotine as a marker of children's contact with nicotine pollution in their environments. We explored the differential associations of these markers with sociodemographics, parental smoking, child TSE, and clinical diagnoses.MethodsData were collected from 276 pediatric emergency department patients (Median age&nbsp;=&nbsp;4.0 years) who lived with a cigarette smoker. Children's hand nicotine and urinary cotinine levels were determined using LC-MS/MS. Parents reported tobacco use and child TSE. Medical records were reviewed to assess discharge diagnoses.ResultsAll children had detectable hand nicotine (GeoM&nbsp;=&nbsp;89.7ng/wipe; 95&nbsp;% CI&nbsp;=&nbsp;[78.9; 102.0]) and detectable urinary cotinine (GeoM&nbsp;=&nbsp;10.4&nbsp;ng/ml; 95%CI&nbsp;=&nbsp;[8.5; 12.6]). Although hand nicotine and urinary cotinine were highly correlated (r&nbsp;=&nbsp;0.62, p&nbsp;&lt;&nbsp;0.001), urinary cotinine geometric means differed between racial groups and were higher for children with lower family income (p&nbsp;&lt;&nbsp;0.05), unlike hand nicotine. Independent of urinary cotinine, age, race, and ethnicity, children with higher hand nicotine levels were at increased risk to have discharge diagnoses of viral/other infectious illness (aOR&nbsp;=&nbsp;7.49; 95%CI&nbsp;=&nbsp;[2.06; 27.24], p&nbsp;=&nbsp;0.002), pulmonary illness (aOR&nbsp;=&nbsp;6.56; 95%CI&nbsp;=&nbsp;[1.76; 24.43], p&nbsp;=&nbsp;0.005), and bacterial infection (aOR&nbsp;=&nbsp;5.45; 95%CI&nbsp;=&nbsp;[1.50; 19.85], p&nbsp;=&nbsp;0.03). In contrast, urinary cotinine levels showed no associations with diagnosis independent of child hand nicotine levels and demographics.DiscussionThe distinct associations of hand nicotine and urinary cotinine suggest the two markers reflect different exposure profiles that contribute differentially to pediatric illness. Because THS in a child's environment directly contributes to hand nicotine, additional studies of children of smokers and nonsmokers are warranted to determine the role of hand nicotine as a marker of THS exposure and its potential role in the development of tobacco-related pediatric illnesses

Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial.

PURPOSE: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response. PATIENTS AND METHODS: A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months. RESULTS: As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5-16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7-14.1) and 9.6 months (95% CI: 4.8-16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders. CONCLUSIONS: The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation

Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer.

BACKGROUND: The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. METHODS: Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000&nbsp;mg, 2550&nbsp;mg, and 3000&nbsp;mg daily in divided doses in addition to cisplatin (at a dose of 100&nbsp;mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56&nbsp;years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5&nbsp;days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19&nbsp;months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. CONCLUSIONS: To the authors knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial