Indoor air pollution and pulmonary performance: investigating errors in exposure assessment

We use pulmonary function measurements on pre-adolescent children and indoor air pollution measurements in the homes of these children to illustrate estimation techniques for linear regression models containing independent variables measured with error. In our data set, replicate measures of indoor air pollutant concentrations provide one method of estimating measurement error variances. Surrogate information in the form of cigarettes smoked is also available for the pollutant of interest. Several estimation procedures are presented, and we combine two estimators, one based on surrogate information and one based on replication information, using generalized least squares.     

Sensitivity analysis for misclassification in logistic regression via likelihood methods and predictive value weighting

The potential for bias due to misclassification error in regression analysis is well understood by statisticians and epidemiologists. Assuming little or no available data for estimating misclassification probabilities, investigators sometimes seek to gauge the sensitivity of an estimated effect to variations in the assumed values of those probabilities. We present an intuitive and flexible approach to such a sensitivity analysis, assuming an underlying logistic regression model. For outcome misclassification, we argue that a likelihood‐based analysis is the cleanest and the most preferable approach. In the case of covariate misclassification, we combine observed data on the outcome, error‐prone binary covariate of interest, and other covariates measured without error, together with investigator‐supplied values for sensitivity and specificity parameters, to produce corresponding positive and negative predictive values. These values serve as estimated weights to be used in fitting the model of interest to an appropriately defined expanded data set using standard statistical software. Jackknifing provides a convenient tool for incorporating uncertainty in the estimated weights into valid standard errors to accompany log odds ratio estimates obtained from the sensitivity analysis. Examples illustrate the flexibility of this unified strategy, and simulations suggest that it performs well relative to a maximum likelihood approach carried out via numerical optimization. Copyright © 2010 John Wiley & Sons, Ltd.     

Secondary school fees and the causal effect of schooling on health behavior

Using German census data, we estimate the causal effect of education on smoking and overweight/obesity using the abolition of secondary school fees as instrumental variable. The West German federal states enacted this reform at different dates after World War II, generating exogenous variation in the access to secondary education. While we find a strong association between schooling and health behaviors using OLS, we do not find support for the notion that education causes better health behavior. Copyright © 2009 John Wiley & Sons, Ltd.     

Psychosocial Factors in the Use of Smokeless Tobacco and Their Implications for P.L. 99-252

This article briefly reviews the prevalence of smokeless tobacco use by males in the United States, the relationship of smokeless tobacco use to cigarette use, and patterns of use that include dosage, topography, products, and function of use. The primary focus of the article is to describe the concurrent and predictive factors associated with onset, use, and cessation of smokeless tobacco. The implications of P.L. 99-252, the Comprehensive Smokeless Tobacco Act of 1986, are discussed in the context of what is known about the psychosocial variables associated with the use of smokeless tobacco.     

The impact of poor health on academic performance: New evidence using genetic markers

This paper examines the influence of health conditions on academic performance during adolescence. To account for the endogeneity of health outcomes and their interactions with risky behaviors we exploit natural variation within a set of genetic markers across individuals. We present evidence that specific genetic markers have good statistical properties to identify the impacts of ADHD, depression and obesity. These markers help reveal a new dynamism from poor health to lower academic achievement with substantial heterogeneity in their impacts across genders. Our investigation further exposes the considerable challenges in identifying health impacts due to the prevalence of comorbid health conditions, with clear implications for the health economics literature.     

Systematic Review and Neural Network Analysis to Define Predictive Variables in Implantable Motor Cortex Stimulation to Treat Chronic Intractable Pain

Implantable motor cortex stimulation (iMCS) has been performed for >25 years to treat various intractable pain syndromes. Its effectiveness is highly variable and, although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment for intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief of >40% as measured by a numerical rating scale (NRS) score. NNA was carried out to predict the outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as the mean accuracy, sensitivity, and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0 and 100%. A total of 358 patients were included (202 males [56.4%]; mean age, 54.2 ±13.3 years), 201 of whom were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified 6 predictive variables that had a relatively high M: 1) the sex of the patient (M = 19.7%); 2) the origin of the lesion (M = 15.1%); 3) the preoperative numerical rating scale score (M = 9.2%); 4) preoperative use of repetitive transcranial magnetic stimulation (M = 7.3%); 5) preoperative intake of opioids (M = 7.1%); and 6) the follow-up period (M = 13.1%). The results from the present study show that these 6 predictive variables influence the outcome of iMCS and that, based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery.PerspectiveThe presented NNA analyzed the functioning of computational models and modeled nonlinear statistical data. Based on this NNA, 6 predictive variables were identified that are suggested to be of importance in the improvement of future iMCS to treat chronic pain.     

Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer (PCa). We correlated quantitative promoter methylation levels of APC, TGFβ2 and RASSF1A in 219 radical prostatectomies diagnosed between 1998 and 2001 with clinicopathological follow-up data available including Gleason Pattern (GP), Gleason Score (GS) and pathological stage and explored their potential in predicting biochemical recurrence using univariate and multivariate analyses. We observed that the average methylation levels of APC increased significantly from GS ≤ 6 to GS7, and pT2 to pT3a, and that of TGFβ2 increased from GS ≤ 6 to GS7, but not for RASSF1A. PCa samples were also stratified into high methylation (HM) and low methylation (LM) groups based on the PMR scores of all cases analyzed for each marker. The HM frequency of APC was greater in pT3a than pT2, and in GS ≥ 8 than GS ≤ 6. The HM frequency also increased significantly from GP3 to GP4 for APC, TGFβ2 and RASSF1A. APC methylation level was a significant predictor of biochemical recurrence in univariate analysis (p-value = 0.028). Finally, we combined methylation data of these three genes with the previously reported novel methylation biomarker HOXD3. Quantitative methylation assessment of a multiplex panel of markers, consisting of APC, HOXD3 and TGFβ2, outperforms any single marker for the prediction of biochemical recurrence (p-value = 0.017). Our study demonstrated that quantitative increase in promoter methylation levels of APC, HOXD3 and TGFβ2 are associated with PCa progression.     

Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics

We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168–175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t → r^′′ transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 Å, with a twist of 90° relative to the equatorial domain, and the root-mean-squared deviation relative to the r^′′ conformer is reduced from 13 to 5 Å, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 Å from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases.     

Testing for linkage and Hardy-Weinberg disequilibrium

This paper concerns several important points when testing for Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) in genetics. First, we challenge the necessity of using exclusively two-sided tests for LD. Next, we show that the exact 2-sided tests based on the most popular measures of LD are not equivalent, and neither are the standard statistical tests even though the 1-sided tests are equivalent. We show how this results in different inference about LD for two data sets consisting of small groups of markers. Finally, we advocate the use of the conditional p-value for both LD and HWE testing. An important advantage of this p-value is that equivalent 1-sided tests are transformed into equivalent 2-sided tests.     

Rethinking TNM: A Breast Cancer Classification to Guide to Treatment and Facilitate Research

Abstract:  The TNM_UICC classification of breast cancer categorizes tumor size, regional lymph node involvement, and distant metastases. Treatment is influenced by these characteristics, but requires knowledge of several other factors. In fact, effective treatment is dependent on disease extent, hormone receptor status, and other biologic characteristics of the cancer. We propose a new classification [tumor node metastasis (TNM)] that not only includes relevant biologic characteristics and can expand to include others as they are validated but also specifies tumor size exactly (T2.3 indicates a cancer of maximum diameter 2.3 cm), provides more information on regional lymph node involvement, and specifies the site(s) of distant metastases. We also propose abolishing the term "carcinoma" for non-invasive neoplastic conditions and the term "infiltrating" for carcinomas. The new classification is sufficiently similar to the TNM_UICC classification to permit valid comparison of patients classified by both systems, but is more logical, provides information useful for guiding therapy, and is flexible enough to satisfy present and future clinical and research needs.