Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end ...points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up.
We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up.
In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions.
Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.
microRNAs (miRNA) repress messenger RNAs post-transcriptionally through binding to the 3' UTR of the mRNA with the miRNA seed region. It has been purported that longer seed regions have a greater ...efficacy on mRNA repression. We tested this hypothesis by evaluating differential expression of miRNAs involved in regulating the immune response, an important mechanism in colorectal cancer (CRC), by seed length category. We subsequently evaluated differential expression of these miRNAs' targets in colonic tissue and the impact of these miRNAs on CRC survival. We determined sequence complementarity between each miRNA seed region and the 3' UTR of each experimentally verified mRNA target gene. We classified miRNAs into groups based on seed regions matching perfectly to a mRNA UTR with six bases beginning at position two, seven bases beginning at position one, seven bases beginning at position two, or eight bases beginning at position one. We analyzed these groups in terms of miRNA differential expression between carcinoma and normal colorectal mucosa, differential colonic target mRNA expression, and risk of dying from CRC. After correction for multiple comparisons, the proportion of the miRNAs that were associated with differential mRNA expression was 0% for the 6-mer, 13.64% for the 7α-mer group, 12.82% for the 7β-mer group, and 8.70% for the 8-mer group. The proportion of miRNAs associated with survival was 20% for the 6-mer group, 27.27% for the 7α-mer group, 10.23% for the 7β-mer group, and 21.74% for the 8-mer group. We did not see a linear relationship between seed length and miRNA expression dysregulation, mRNA expression, or survival. Our findings do not support the hypothesis the seed region length alone influences mRNA repression.
When genomics researchers design a high-throughput study to test for differential expression, some biological systems and research questions provide opportunities to use paired samples from subjects, ...and researchers can plan for a certain proportion of subjects to have paired samples. We consider the effect of this paired samples proportion on the statistical power of the study, using characteristics of both count (RNA-Seq) and continuous (microarray) expression data from a colorectal cancer study.
We demonstrate that a higher proportion of subjects with paired samples yields higher statistical power, for various total numbers of samples, and for various strengths of subject-level confounding factors. In the design scenarios considered, the statistical power in a fully-paired design is substantially (and in many cases several times) greater than in an unpaired design.
For the many biological systems and research questions where paired samples are feasible and relevant, substantial statistical power gains can be achieved at the study design stage when genomics researchers plan on using paired samples from the largest possible proportion of subjects. Any cost savings in a study design with unpaired samples are likely accompanied by underpowered and possibly biased results.
The Human Connectome Project (HCP) has developed protocols, standard operating and quality control procedures, and a suite of informatics tools to enable high throughput data collection, data ...sharing, automated data processing and analysis, and data mining and visualization. Quality control procedures include methods to maintain data collection consistency over time, to measure head motion, and to establish quantitative modality-specific overall quality assessments. Database services developed as customizations of the XNAT imaging informatics platform support both internal daily operations and open access data sharing. The Connectome Workbench visualization environment enables user interaction with HCP data and is increasingly integrated with the HCP's database services. Here we describe the current state of these procedures and tools and their application in the ongoing HCP study.
•HCP quality control procedures have enabled high throughout data acquisition.•HCP database services enable operations and open access data sharing.•Connectome Workbench enables cross-modal data visualization and exploration.
Blood pressure (BP) control rates among US adults taking antihypertensive medication have not increased over the past decade. Many adults require 2 or more classes of antihypertensive medication to ...achieve guideline-recommended BP goals, but the proportion of US adults taking antihypertensive medication monotherapy, versus combination therapy, has not been quantified using contemporary data. We analyzed data from 2005 to 2008, 2009 to 2012, and 2013 to 2016 National Health and Nutrition Examination Surveys to determine trends in monotherapy and combinations of antihypertensive medication classes among US adults age ≥20 years with hypertension taking antihypertensive medication (n=7837). The proportion of US adults taking antihypertensive medication with uncontrolled BP (ie, systolic BP ≥140 or diastolic BP ≥90 mm Hg) was 32.3%, 30.2%, and 31.0% in 2005 to 2008, 2009 to 2012, and 2013 to 2016, respectively (Ptrend=0.37). Between 2005 to 2008 and 2013 to 2016, there was no evidence of changes in the proportions of US adults taking antihypertensive monotherapy (39.5%–40.4%, Ptrend=0.67), dual-therapy (37.9%–38.3%, Ptrend=0.75), triple-therapy (17.6%–16.5%, Ptrend=0.36), or quadruple-therapy (4.4%–4.3%, Ptrend=0.93). Between 2005 to 2008 and 2013 to 2016, there was no evidence of changes in the proportions of US adults with uncontrolled BP taking antihypertensive monotherapy (39.3%–40.6%, Ptrend=0.78). A high proportion of US adults with hypertension, including those with uncontrolled BP, are taking one antihypertensive medication class. Increasing the use of dual- and triple-therapy antihypertensive medication regimens may restore the upward trend in BP control rates among US adults.
MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on ...few individuals and imprecise. In this study, we utilize population‐based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa‐miR‐145‐5p and hsa‐miR‐31‐5p showed increased expression with more advanced tumor stage, while hsa‐miR‐200b‐3p, hsa‐miR‐215 and hsa‐miR‐451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa‐miR‐145‐3p hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61, and hsa‐miR‐9‐3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa‐miR‐335‐5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa‐miR‐374a‐5p, hsa‐miR‐570‐3p and hsa‐miR‐18a‐5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.
What's new?
MicroRNAs (miRNAs) are promising prognostic biomarkers in colorectal cancer, but more work is needed to identify clinically meaningful stage‐ and survival‐specific associations. The present study attempted to identify those associations for 121 miRNAs using population‐based data for more than 1,140 colorectal cancer patients. Microarray and statistical analyses uncovered five miRNAs associated specifically with more advanced colorectal cancer. Another 25 miRNAs were linked to mortality for either colon cancer or rectal cancer. The large number of patients and the incorporation of data on tumor molecular phenotype facilitated the detection of associations for miRNAs infrequently expressed in the study population.
We examined expression of genes in the p53-signaling pathway. We determine if genes that have significantly different expression in carcinoma tissue compared to normal mucosa also have significantly ...differentially expressed miRNAs. We utilize a sample of 217 CRC cases.
We focused on fold change (FC) > 1.50 or <0.67 for genes and miRNAs, that were statistically significant after adjustment for multiple comparisons. We evaluated the linear association between the differential expression of miRNA and mRNA. miRNA:mRNA seed-region matches also were determined.
Eleven dysregulated genes were associated with 37 dysregulated miRNAs; all were down-stream from the TP53 gene. MiR-150-5p (HR = 0.82) and miR-196b-5p (HR 0.73) significantly reduced the likelihood of dying from CRC when miRNA expression increased in rectal tumors.
Our data suggest that activation of p53 from cellular stress, could target downstream genes that in turn could influence cell cycle arrest, apoptosis, and angiogenesis through mRNA:miRNA interactions.
Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to ...evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA‐Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of ≥1.5 or ≤0.67) that were statistically significant after adjustment for multiple comparisons. Of the 74 TSGs evaluated, 22 were associated with carcinoma/normal mucosa differential expression. Ten TSGs were up‐regulated (FAM123B, RB1, TP53, RUNX1, MSH2, BRCA1, BRCA2, SOX9, NPM1, and RNF43); six TSGs were down‐regulated (PAX5, IZKF1, GATA3, PRDM1, TET2, and CYLD); four were associated with MSI tumors (MLH1, PTCH1, and CEBPA down‐regulated and MSH6 up‐regulated); and two were associated with MSS tumors (PHF6 and ASXL1 up‐regulated). Thirteen of these TSGs were associated with 44 miRNAs. Twenty‐seven of the 59 OGs evaluated were dysregulated: 14 down‐regulated (KLF4, BCL2, SSETBP1, FGFR2, TSHR, MPL, KIT, PDGFRA, GNA11, GATA2, FGFR3, AR, CSF1R, and JAK3), seven up‐regulated (DNMT1, EZH2, PTPN11, SKP2, CCND1, MET, and MYC); three down‐regulated for MSI (FLT3, CARD11, and ALK); two up‐regulated for MSI (IDH2 and HRAS); and one up‐regulated with MSS tumors (CTNNB1). These findings suggest possible co‐regulatory function between TSGs, OGs, and miRNAs, involving both direct and indirect associations that operate through feedback and feedforward loops.
Introduction
Current literature reveals that up to 88% of individuals undergoing behavioral speech therapy (BST) for chronic refractory cough (CRC) demonstrate benefit at 4–8 weeks post-treatment. ...However, investigations of BST are confounded by overlapping use of neuromodulators, missing follow-up data, and an absence of long-term outcomes. This study investigated treatment outcomes beyond 6 months in individuals diagnosed with CRC, and whose treatment outcomes were clinically undocumented.
Methods
Participants with CRC 6 months or greater beyond treatment completion were recruited. Participants completed a post-treatment Leicester Cough Questionnaire (LCQ) and a telephone interview. Demographic data, cough characteristics, treatment adherence, BST outcomes, and pre- and post-treatment LCQ scores were evaluated.
Results
80 individuals met inclusion criteria and 29 consented to participate. Of these, 27 were recommended BST. The majority were female (19/27) with average age of 58 years (SD = 12). Mean cough duration was 60 months (SD = 98) and mean post-BST duration was 20 months (SD = 9). A significant increase in pre- to post-treatment LCQ scores occurred 4.4 (SD = 4.2) (
p
< 0.0001).
Conclusion
This study addressed long-term BST benefit for CRC and demonstrated a significant improvement in long-term post-treatment LCQ total scores more than a year after BST for CRC. More than half of participants indicated improvement or elimination of their cough. These findings further support the benefit of BST for CRC. Future research should consider patient perspectives about treatment outcomes given that 44% of participants reported no benefit from BST.
Apoptosis is genetically regulated and involves intrinsic and extrinsic pathways. We examined 133 genes within these pathways to identify whether they are expressed differently in colorectal ...carcinoma (CRC) and normal tissue (N = 217) and if they are associated with similar differential miRNA expression. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0) were generated. We focused on dysregulated genes with a fold change (FC) of > 1.50 or < 0.67, that were significant after adjustment for multiple comparisons. miRNA:mRNA seed-region matches were determined. Twenty-three genes were significantly downregulated (FC < 0.67) and 18 were significantly upregulated (FC > 1.50). Of these 41 genes, 11 were significantly associated with miRNA differential expression.
BIRC5
had the greatest number of miRNA associations (14) and the most miRNAs with a seed-region match (10). Four of these matches, miR-145-5p, miR-150-5p, miR-195-5p, and miR-650, had a negative beta coefficient.
CSF2RB
was associated with ten total miRNAs (five with a seed-region match, and one miRNA, miR-92a-3p, with a negative beta coefficient). Of the three miRNAs associated with
CTSS
, miR-20b-5p, and miR-501-3p, had a seed-region match and a negative beta coefficient between miRNA:mRNA pairs. Several miRNAs that were associated with dysregulated gene expression, seed-region matches, and negative beta coefficients also were associated with CRC-specific survival. Our data suggest that miRNAs could influence several apoptosis-related genes.
BIRC5, CTSS
, and
CSF2R
all had seed-region matches with miRNAs that would favor apoptosis. Our study identifies several miRNA associated with apoptosis-related genes, that if validated, could be important therapeutic targets.
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