Systematic clustering of transcription start site landscapes

Genome-wide, high-throughput methods for transcription start site (TSS) detection have shown that most promoters have an array of neighboring TSSs where some are used more than others, forming a distribution of initiation propensities. TSS distributions (TSSDs) vary widely between promoters and earlier studies have shown that the TSSDs have biological implications in both regulation and function. However, no systematic study has been made to explore how many types of TSSDs and by extension core promoters exist and to understand which biological features distinguish them. In this study, we developed a new non-parametric dissimilarity measure and clustering approach to explore the similarities and stabilities of clusters of TSSDs. Previous studies have used arbitrary thresholds to arrive at two general classes: broad and sharp. We demonstrated that in addition to the previous broad/sharp dichotomy an additional category of promoters exists. Unlike typical TATA-driven sharp TSSDs where the TSS position can vary a few nucleotides, in this category virtually all TSSs originate from the same genomic position. These promoters lack epigenetic signatures of typical mRNA promoters and a substantial subset of them are mapping upstream of ribosomal protein pseudogenes. We present evidence that these are likely mapping errors, which have confounded earlier analyses, due to the high similarity of ribosomal gene promoters in combination with known G addition bias in the CAGE libraries. Thus, previous two-class separations of promoter based on TSS distributions are motivated, but the ultra-sharp TSS distributions will confound downstream analyses if not removed.This work was supported by a grant from the Novo Nordisk Foundation, http://www.novonordiskfonden.dk/. The European Research Council (http:// erc.europa.eu/) has provided financial support to Dr. Sandelin under the EU 7th Framework Programme (FP7/2007-2013)/ERC grant agreement 204135

Systematic clustering of transcription start site landscapes

Genome-wide, high-throughput methods for transcription start site (TSS) detection have shown that most promoters have an array of neighboring TSSs where some are used more than others, forming a distribution of initiation propensities. TSS distributions (TSSDs) vary widely between promoters and earlier studies have shown that the TSSDs have biological implications in both regulation and function. However, no systematic study has been made to explore how many types of TSSDs and by extension core promoters exist and to understand which biological features distinguish them. In this study, we developed a new non-parametric dissimilarity measure and clustering approach to explore the similarities and stabilities of clusters of TSSDs. Previous studies have used arbitrary thresholds to arrive at two general classes: broad and sharp. We demonstrated that in addition to the previous broad/sharp dichotomy an additional category of promoters exists. Unlike typical TATA-driven sharp TSSDs where the TSS position can vary a few nucleotides, in this category virtually all TSSs originate from the same genomic position. These promoters lack epigenetic signatures of typical mRNA promoters and a substantial subset of them are mapping upstream of ribosomal protein pseudogenes. We present evidence that these are likely mapping errors, which have confounded earlier analyses, due to the high similarity of ribosomal gene promoters in combination with known G addition bias in the CAGE libraries. Thus, previous two-class separations of promoter based on TSS distributions are motivated, but the ultra-sharp TSS distributions will confound downstream analyses if not removed

Translation and Validation of the Finnish Version of the Patient-Rated Wrist Evaluation Questionnaire (PRWE) in Patients with Acute Distal Radius Fracture

Background and Aims: Patient-rated outcome measures have become increasingly important in clinical research. They provide research and clinical tools which can be utilized in the assessment of patient recovery and treatment efficacy. The purpose of our study was to translate and validate the original version of the PRWE form into Finnish. Material and Methods: We conducted the translation of the PRWE questionnaire according to standardized guidelines. Patients (N=119) with an acute distal radius fracture were recruited, and they completed the PRWE and QuickDASH questionnaires at 2months and 4months after the wrist injury. Results: The mean answering times were 52days (standard deviation [SD] 9.8 days) and 116days (standard deviation [SD] 14.8 days), respectively. Both the internal consistency (Cronbach's alpha) of 0.976 and the intraclass correlation coefficient (ICC) of 0.992 (95% CI 0.966-0.998) showed excellent reliability for the total PRWE score. The correlation coefficients between the total score, the subscales, and for improvement over time for PRWE and QuickDASH were excellent. The responsiveness was good with an effect size of 0.83 and a standard response mean of 1.22. Conclusion: Our study shows that the Finnish version of the PRWE is reliable, valid, and responsive for the evaluation of pain and disability after distal radius fracture.Peer reviewe

Longitudinal Validity and Minimal Important Change for the Modified Lower Extremity Functional Scale (LEFS) in Orthopedic Foot and Ankle Patients

The lower extremity functional scale (LEFS) is a patient-reported outcome measure for lower extremity disorders. Aim of this study was to assess the longitudinal validity including responsiveness and test-retest reliability of the revised 15-item version, and to define the minimal important change (MIC) of the modified LEFS in a generic sample of orthopedic foot and ankle patients who underwent surgery. Responsiveness, effect size, and standardized response mean were measured by determining the score change between the baseline and 6 months administration of the LEFS from 156 patients. There was no significant difference between preoperative (median 78, interquartile range [IQR] 64.2-90.3) and postoperative (median 75.0, IQR 61.7-95.0) scores. Both effect size and standardized response mean were low (0.06 and 0.06, respectively). Test-retest reliability of the LEFS was satisfactory. Intraclass correlation coefficient was 0.85 (95% confidence interval 0.81-0.88). MIC value could not be estimated due to the lack of significant score change. The modified LEFS presented with relatively low longitudinal validity in a cohort of generic orthopedic foot and ankle patients. The findings of this study indicate that the modified LEFS might not be the optimal instrument in assessing the clinical change over time for these patients. (c) 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

Structural and Construct Validity of the Foot and Ankle Ability Measure (FAAM) With an Emphasis on Pain and Functionality After Foot Surgery : A Multicenter Study

The Foot and Ankle Ability Measure (FAAM) is a patient-reported outcome measure that is available in several languages. We aim to assess the structural and construct validity of the FAAM with an emphasis on pain and functionality after foot surgery. The activities of daily living (ADL) and Sports subscales of the Finnish version of the FAAM were completed by 182 patients who underwent operative treatment for disorders of the foot. Convergent validity was assessed by principal component analysis using Spearman's correlation coefficient between the FAAM subscales and the principal components (Function-PC and Pain-PC) derived from validated patient-reported outcome measures. Subscales were studied for floor and ceiling effects, internal consistency and unidimensionality. Internal consistency was examined with Cronbach's alpha and the subscale structure with exploratory factor analysis. FAAM-ADL had high correlation with the Function-PC (r = 0.87, 95% confidence interval [CI] 0.81-0.91) and the Pain-PC (r = 0.75, 95% CI 0.65-0.83). FAAM-Sports had moderate correlation (r = 0.64, 95% CI 0.50-0.74) with the Function-PC and high correlation (r = 0.74, 95% CI 0.64-0.82) with the Pain-PC. No floor or ceiling effects were observed. Cronbach's alpha was 0.97 (95% CI 0.96-0.98) for the ADL and 0.93 (95% CI 0.91-0.95) for the Sports subscales. The results supported the unidimensionality of the FAAM-Sports. Within the ADL subscale, 3 factors were identified, suggesting a 3-factor model for the FAAM overall. Results highlighted the inter-relationship of pain and physical function. Further research on longitudinal validity is needed. (C) 2021 The Author(s).Peer reviewe

GimmeMotifs: a de novo motif prediction pipeline for ChIP-sequencing experiments

Summary: Accurate prediction of transcription factor binding motifs that are enriched in a collection of sequences remains a computational challenge. Here we report on GimmeMotifs, a pipeline that incorporates an ensemble of computational tools to predict motifs de novo from ChIP-sequencing (ChIP-seq) data. Similar redundant motifs are compared using the weighted information content (WIC) similarity score and clustered using an iterative procedure. A comprehensive output report is generated with several different evaluation metrics to compare and evaluate the results. Benchmarks show that the method performs well on human and mouse ChIP-seq datasets. GimmeMotifs consists of a suite of command-line scripts that can be easily implemented in a ChIP-seq analysis pipeline

oPOSSUM: integrated tools for analysis of regulatory motif over-representation

The identification of over-represented transcription factor binding sites from sets of co-expressed genes provides insights into the mechanisms of regulation for diverse biological contexts. oPOSSUM, an internet-based system for such studies of regulation, has been improved and expanded in this new release. New features include a worm-specific version for investigating binding sites conserved between Caenorhabditis elegans and C. briggsae, as well as a yeast-specific version for the analysis of co-expressed sets of Saccharomyces cerevisiae genes. The human and mouse applications feature improvements in ortholog mapping, sequence alignments and the delineation of multiple alternative promoters. oPOSSUM2, introduced for the analysis of over-represented combinations of motifs in human and mouse genes, has been integrated with the original oPOSSUM system. Analysis using user-defined background gene sets is now supported. The transcription factor binding site models have been updated to include new profiles from the JASPAR database. oPOSSUM is available at http://www.cisreg.ca/oPOSSUM

An intuitionistic approach to scoring DNA sequences against transcription factor binding site motifs

Background: Transcription factors (TFs) control transcription by binding to specific regions of DNA called transcription factor binding sites (TFBSs). The identification of TFBSs is a crucial problem in computational biology and includes the subtask of predicting the location of known TFBS motifs in a given DNA sequence. It has previously been shown that, when scoring matches to known TFBS motifs, interdependencies between positions within a motif should be taken into account. However, this remains a challenging task owing to the fact that sequences similar to those of known TFBSs can occur by chance with a relatively high frequency. Here we present a new method for matching sequences to TFBS motifs based on intuitionistic fuzzy sets (IFS) theory, an approach that has been shown to be particularly appropriate for tackling problems that embody a high degree of uncertainty. Results: We propose SCintuit, a new scoring method for measuring sequence-motif affinity based on IFS theory. Unlike existing methods that consider dependencies between positions, SCintuit is designed to prevent overestimation of less conserved positions of TFBSs. For a given pair of bases, SCintuit is computed not only as a function of their combined probability of occurrence, but also taking into account the individual importance of each single base at its corresponding position. We used SCintuit to identify known TFBSs in DNA sequences. Our method provides excellent results when dealing with both synthetic and real data, outperforming the sensitivity and the specificity of two existing methods in all the experiments we performed. Conclusions: The results show that SCintuit improves the prediction quality for TFs of the existing approaches without compromising sensitivity. In addition, we show how SCintuit can be successfully applied to real research problems. In this study the reliability of the IFS theory for motif discovery tasks is proven

Structural validity of the foot and ankle outcome score for orthopaedic pathologies with Rasch Measurement Theory

Publisher Copyright: © 2021 The AuthorsA B S T R A C T Background: The Foot and Ankle Outcome Score (FAOS) is one of the most frequently used patient reported outcome measures for foot and ankle conditions. The aim is to test the structural validity of the Finnish version of the FAOS using Rasch Measurement Theory. Methods: FAOS scores were obtained from 218 consecutive patients who received operative treatment for foot and ankle conditions. The FAOS data were fitted into the Rasch model and person separation index (PSI) calculated. Results: All the five subscales provided good coverage and targeting. Three subscales presented unidimensional structure. Thirty-eight of the 42 items had ordered response category thresholds. Three of the 42 items had differential item functioning towards gender. All subscales showed sufficient fit to the Rasch model. PSI ranged from 0.73 to 0.94 for the subscales. Conclusions: The Finnish version of the FAOS shows acceptable structural validity for assessing complaints in orthopaedic foot and ankle patients. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Foot and Ankle Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer reviewe