Marginal Regression Modeling under Irregular, Biased Sampling

In longitudinal studies observations are often obtained at continuous subject-specific times. Frequently the availability of outcome data may be related to the outcome measure or other covariates that are related to the outcome measure. Under such biased sampling designs unadjusted regression analysis yield biased estimates. Building on the work of Lin & Ying (2001) that integrates counting processes techniques with longitudinal data settings we propose a class of estimators that can handle biased sampling. We call those estimators ``inverse--intensity--rate--ratio--weighted\u27\u27 (IIRR) estimators. Of major focus is a mean--response model where we examine the marginal effect of the covariate X at time t on the mean of the response Y at that time. The proposed class of closed-form estimators are root n-consistent and asymptotically normal and do not require estimating any infinite--dimensional parameters. The estimators and estimators of their variance are relatively simple and computationally feasible. Simulation studies demonstrate that asymptotic approximations are accurate for moderate sample sizes. %Also, when comparing squared error, the proposed estimators are largely favored when compared to the Lin and Ying estimates or the GEE estimates. We illustrate our approach using data from a health service research study with extreme noncompliance to the scheduled visits that can not be explained by the intervention assignment alone

Longitudinal Data Analysis for Generalized Linear Models under Irregular, Biased Sampling: Situations with Follow-up Dependent on Outcome or Auxiliary Outcome-related Variables

In longitudinal studies, observations are often obtained at subject-specific observation times. Those times can be continuous times, not at a set of prespecified times. Frequently the observation times may be related to the outcome measure or other auxiliary variables that are related to the outcome measure but undesirable to condition upon in the regression model for outcome. Regression analysis unadjusted for such sampling designs yield biased estimates. Based on estimating equations, we propose a class of estimators in generalized linear regression models that can handle biased sampling under continuous observation times. We call those estimators ``inverse--intensity rate--ratio--weighted\u27\u27 (IIRR) estimators. The proposed estimators are simple and easily computed as they are readily available in many statistical software packages. We integrate counting processes techniques with longitudinal data settings. We leave stochastic structure of the outcome completely unspecified. Covariates modeling the association in the regression model for outcome as well as covariates predicting the observation times can contain lagged outcome or lagged covariates. The estimators are root n consistent and asymptotically normal. We avoid estimation of the infinite--dimensional baseline sampling intensity. The finite sample performance of the proposed estimation procedure is investigated in a simulation study. Finally, we illustrate our approach with a data set from a health services research study that was subject to high noncompliance to predefined visit times

Semiparametric Loglinear Regression for Longitudinal Measurements Subject to Irregular, Biased Follow-up

We propose a method for analysis of loglinear regression models for longitudinal data that are subject to continuous and irregular follow-up. Frequently, if the follow-up is irregular, the availability of outcome data may be related to the outcome measure or other covariates that are related to the outcome measure. Under such biased sampling designs unadjusted regression analysis yield biased estimates. We examine the marginal association of the covariates X at time t and the logarithm of the mean of response Y at time t. We focus on semiparametric regression with unspecified baseline function of time. To predict the follow-up times we use a marginal rate model with arbitrary baseline intensity and possibly time-varying covariates Z. We avoid the estimation of infinitely dimensional baseline intensity of follow-up as well as the intercept function in the outcome model. Our estimation procedure is based on estimating equations. The proposed class of estimators are root n consistent and asymptotically normal. We present simulation studies that assess the performance of the estimator under finite samples. We illustrate our approach using data from a health services research study

THE EFFECT OF FLUID ACCUMULATION IN STOMACH ON ELECTRICAL IMPEDANCE TOMOGRAPHY IMAGE OF LUNGS

Electrical impedance tomography (EIT) is a non-invasive, side effect free, bedside monitoring alternative to conventional imaging methods. One of the most frequent EIT system used for lung monitoring is PulmoVista 500 (Dräger Medical, Germany). The manufacturer of the system recommends placing the electrode belt at the level of 4th to 6th intercostal space. Since the fundus or cardia of the stomach is located in a position that contributes to the creation of EIT lung image, there is a question whether the EIT image is not influenced by the content of the stomach. The aim of this study is to investigate whether significantly different EIT images of the lungs can be obtained, if the monitoring is performed in subjects with different liquid content in the stomach. Eleven healthy subjects were monitored in this study at three phases: with empty stomach, after drinking 0.5 L and 1.0 L of water. Significant changes in the distribution of ventilation were found for regions of interest set as quadrants

Panel Count Data Regression with Informative Observation Times

When patients are monitored for potentially recurrent events such as infections or tumor metastases, it is common for clinicians to ask patients to come back sooner for follow-up based on the results of the most recent exam. This means that subjects’ observation times will be irregular and related to subject-specific factors. Previously proposed methods for handling such panel count data assume that the dependence between the events process and the observation time process is time-invariant. This article considers situations where the observation times are predicted by time-varying factors, such as the outcome observed at the last visit or cumulative exposure. Using a joint modeling approach, we propose a class of inverse-intensity-rate-ratio weighted estimators that are root n consistent and asymptotically normal. The proposed estimators use estimating equations and are fairly simple and easy to compute. We demonstrate the performance of the method using simulated data and illustrate the approach using a cancer study dataset

Participatory budgeting in Brno – inspiration for other cities?

Purpose: Literature offers many benefits associated with participatory budgeting. However, the implementation of participatory budgeting (influenced by many factors) is unique in every country, and it cannot be linked only to advantages. Presenting the advantages and disadvantages of participatory budgeting can extend the theoretical knowledge and better understand this field. The purpose of this paper is to evaluate the development of participatory budgeting in the Czech Republic. It focuses on the implementation and results of participatory budgeting in Brno's city (the second-largest city in the Czech Republic), which introduced the concept in 2017. Design/Methodology/Approach: The analysis of participatory budgeting is based on a critical analysis of recent literature. In the empirical part, we focused on the implementation of participatory budgeting in Brno. We have analyzed a few factors: voting results, the size of the participatory budget, and winning projects. A qualitative method was applied to synthesize this research. Findings: When assessing participatory budgeting in Brno, we identified both the positive and negative aspects of its implementation. To sum up, we have observed that during the three years of participatory budgeting in Brno, the negative aspects outweighed the positive aspects. Practical Implications: This study's results can help other municipalities of similar size with a decision whether (and how) to implement participatory budgeting. Likewise, it can help other cities to avoid some mistakes. Originality/Value: This paper extends existing findings mentioned in many scientific studies by referring to the Czech experience where negative aspects of participatory budgeting can outweigh its positive aspects.peer-reviewe

Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity : a study of young healthy MZ twins

Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes. We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference Delta BMI ae 3 kg/m(2)) and concordant (n = 5, Delta BMI <3 kg/m(2)) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals. The heavier (BMI 29.9 +/- 1.0 kg/m(2)) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p <0.01 for all measures) than the lighter (24.1 +/- 0.9 kg/m(2)) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p <0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1 alpha (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p <0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals. Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways. The datasets analysed and generated during the current study are available in the figshare repository.Peer reviewe

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

Modified Atkins diet induces subacute selective ragged-red-fiber lysis in mitochondrial myopathypatients

Mitochondrial myopathy (MM) with progressive external ophthalmoplegia (PEO) is a common manifestation of mitochondrial disease in adulthood, for which there is no curative therapy. In mice with MM, ketogenic diet significantly delayed progression of the disease. We asked in this pilot study what effects high-fat, low-carbohydrate modified Atkins diet (mAD) had for PEO/MM patients and control subjects and followed up the effects by clinical, morphological, transcriptomic, and metabolomic analyses. All of our five patients, irrespective of genotype, showed a subacute response after 1.5-2weeks of diet, with progressive muscle pain and leakage of muscle enzymes, leading to premature discontinuation of the diet. Analysis of muscle ultrastructure revealed selective fiber damage, especially in the ragged-red-fibers (RRFs), a MM hallmark. Two years of follow-up showed improvement of muscle strength, suggesting activation of muscle regeneration. Our results indicate that (i) nutrition can modify mitochondrial disease progression, (ii) dietary counseling should be part of MM care, (iii) short mAD is a tool to induce targeted RRF lysis, and (iv) mAD, a common weight-loss method, may induce muscle damage in a population subgroup.Peer reviewe