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1.  DelPhi Web Server: A comprehensive online suite for electrostatic calculations of biological macromolecules and their complexes 
Here we report a web server, the DelPhi web server, which utilizes DelPhi program to calculate electrostatic energies and the corresponding electrostatic potential and ionic distributions, and dielectric map. The server provides extra services to fix structural defects, as missing atoms in the structural file and allows for generation of missing hydrogen atoms. The hydrogen placement and the corresponding DelPhi calculations can be done with user selected force field parameters being either Charmm22, Amber98 or OPLS. Upon completion of the calculations, the user is given option to download fixed and protonated structural file, together with the parameter and Delphi output files for further analysis. Utilizing Jmol viewer, the user can see the corresponding structural file, to manipulate it and to change the presentation. In addition, if the potential map is requested to be calculated, the potential can be mapped onto the molecule surface. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
PMCID: PMC3966485  PMID: 24683424
DelPhi; electrostatics; proteins; continuum models; electrostatic potential; Finite-Difference Poisson-Boltzmann solver
2.  DelPhi web server v2: incorporating atomic-style geometrical figures into the computational protocol 
Bioinformatics  2012;28(12):1655-1657.
Summary: A new edition of the DelPhi web server, DelPhi web server v2, is released to include atomic presentation of geometrical figures. These geometrical objects can be used to model nano-size objects together with real biological macromolecules. The position and size of the object can be manipulated by the user in real time until desired results are achieved. The server fixes structural defects, adds hydrogen atoms and calculates electrostatic energies and the corresponding electrostatic potential and ionic distributions.
Availability and implementation: The web server follows a client–server architecture built on PHP and HTML and utilizes DelPhi software. The computation is carried out on supercomputer cluster and results are given back to the user via http protocol, including the ability to visualize the structure and corresponding electrostatic potential via Jmol implementation. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
Contact: nsmith@clemson.edu, ealexov@clemson.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts200
PMCID: PMC3371833  PMID: 22531215
3.  Highly efficient and exact method for parallelization of grid-based algorithms and its implementation in DelPhi 
Journal of computational chemistry  2012;33(24):1960-1966.
The Gauss-Seidel method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the Gauss-Seidel method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of CPUs. In contrast to other existing solutions, our method does not require any assumptions and is equally applicable for solving linear and nonlinear equations. This approach is implemented in the DelPhi program, which is a finite difference Poisson-Boltzmann equation solver to model electrostatics in molecular biology. This development makes the iterative procedure on obtaining the electrostatic potential distribution in the parallelized DelPhi several folds faster than that in the serial code. Further we demonstrate the advantages of the new parallelized DelPhi by computing the electrostatic potential and the corresponding energies of large supramolecular structures.
doi:10.1002/jcc.23033
PMCID: PMC3412928  PMID: 22674480
electrostatics; DelPhi; Poisson- Boltzmann equation; Gauss-Seidel iteration; parallel computing
4.  A general and Robust Ray-Casting-Based Algorithm for Triangulating Surfaces at the Nanoscale 
PLoS ONE  2013;8(4):e59744.
We present a general, robust, and efficient ray-casting-based approach to triangulating complex manifold surfaces arising in the nano-bioscience field. This feature is inserted in a more extended framework that: i) builds the molecular surface of nanometric systems according to several existing definitions, ii) can import external meshes, iii) performs accurate surface area estimation, iv) performs volume estimation, cavity detection, and conditional volume filling, and v) can color the points of a grid according to their locations with respect to the given surface. We implemented our methods in the publicly available NanoShaper software suite (www.electrostaticszone.eu). Robustness is achieved using the CGAL library and an ad hoc ray-casting technique. Our approach can deal with any manifold surface (including nonmolecular ones). Those explicitly treated here are the Connolly-Richards (SES), the Skin, and the Gaussian surfaces. Test results indicate that it is robust to rotation, scale, and atom displacement. This last aspect is evidenced by cavity detection of the highly symmetric structure of fullerene, which fails when attempted by MSMS and has problems in EDTSurf. In terms of timings, NanoShaper builds the Skin surface three times faster than the single threaded version in Lindow et al. on a 100,000 atoms protein and triangulates it at least ten times more rapidly than the Kruithof algorithm. NanoShaper was integrated with the DelPhi Poisson-Boltzmann equation solver. Its SES grid coloring outperformed the DelPhi counterpart. To test the viability of our method on large systems, we chose one of the biggest molecular structures in the Protein Data Bank, namely the 1VSZ entry, which corresponds to the human adenovirus (180,000 atoms after Hydrogen addition). We were able to triangulate the corresponding SES and Skin surfaces (6.2 and 7.0 million triangles, respectively, at a scale of 2 grids per Å) on a middle-range workstation.
doi:10.1371/journal.pone.0059744
PMCID: PMC3618509  PMID: 23577073
5.  GPU linear and non-linear Poisson–Boltzmann solver module for DelPhi 
Bioinformatics  2013;30(4):569-570.
Summary: In this work, we present a CUDA-based GPU implementation of a Poisson–Boltzmann equation solver, in both the linear and non-linear versions, using double precision. A finite difference scheme is adopted and made suitable for the GPU architecture. The resulting code was interfaced with the electrostatics software for biomolecules DelPhi, which is widely used in the computational biology community. The algorithm has been implemented using CUDA and tested over a few representative cases of biological interest. Details of the implementation and performance test results are illustrated. A speedup of ∼10 times was achieved both in the linear and non-linear cases.
Availability and implementation: The module is open-source and available at http://www.electrostaticszone.eu/index.php/downloads.
Contact: walter.rocchia@iit.it
Supplementary information: Supplementary data are available at Bioinformatics online
doi:10.1093/bioinformatics/btt699
PMCID: PMC3928518  PMID: 24292939
6.  dMM-PBSA: A New HADDOCK Scoring Function for Protein-Peptide Docking 
Molecular-docking programs coupled with suitable scoring functions are now established and very useful tools enabling computational chemists to rapidly screen large chemical databases and thereby to identify promising candidate compounds for further experimental processing. In a broader scenario, predicting binding affinity is one of the most critical and challenging components of computer-aided structure-based drug design. The development of a molecular docking scoring function which in principle could combine both features, namely ranking putative poses and predicting complex affinity, would be of paramount importance. Here, we systematically investigated the performance of the MM-PBSA approach, using two different Poisson–Boltzmann solvers (APBS and DelPhi), in the currently rising field of protein-peptide interactions (PPIs), identifying the correct binding conformations of 19 different protein-peptide complexes and predicting their binding free energies. First, we scored the decoy structures from HADDOCK calculation via the MM-PBSA approach in order to assess the capability of retrieving near-native poses in the best-scoring clusters and of evaluating the corresponding free energies of binding. MM-PBSA behaves well in finding the poses corresponding to the lowest binding free energy, however the built-in HADDOCK score shows a better performance. In order to improve the MM-PBSA-based scoring function, we dampened the MM-PBSA solvation and coulombic terms by 0.2, as proposed in the HADDOCK score and LIE approaches. The new dampened MM-PBSA (dMM-PBSA) outperforms the original MM-PBSA and ranks the decoys structures as the HADDOCK score does. Second, we found a good correlation between the dMM-PBSA and HADDOCK scores for the near-native clusters of each system and the experimental binding energies, respectively. Therefore, we propose a new scoring function, dMM-PBSA, to be used together with the built-in HADDOCK score in the context of protein-peptide docking simulations.
doi:10.3389/fmolb.2016.00046
PMCID: PMC5006095  PMID: 27630991
MM-PBSA; scoring function; binding free energies; haddock; protein-peptide interaction
7.  Modeling the Electrostatic Potential of Asymmetric Lipopolysaccharide Membranes: The MEMPOT Algorithm Implemented in DelPhi 
Journal of computational chemistry  2014;35(19):1418-1429.
Four chemotypes of the Rough lipopolysaccharides (LPS) membrane from Pseudomonas aeruginosa were investigated by a combined approach of explicit water molecular dynamics (MD) simulations and Poisson-Boltzmann continuum electrostatics with the goal to deliver the distribution of the electrostatic potential across the membrane. For the purpose of this investigation, a new tool for modeling the electrostatic potential profile along the axis normal to the membrane, MEMPOT, was developed and implemented in DelPhi. Applying MEMPOT on the snapshots obtained by MD simulations, two observations were made: (a) the average electrostatic potential has a complex profile, but is mostly positive inside the membrane due to the presence of Ca2+ ions which overcompensate for the negative potential created by lipid phosphate groups; and (b) correct modeling of the electrostatic potential profile across the membrane requires taking into account the water phase, while neglecting it (vacuum calculations) results in dramatic changes including a reversal of the sign of the potential inside the membrane. Furthermore, using DelPhi to assign different dielectric constants for different regions of the LPS membranes, it was investigated whether a single frame structure before MD simulations with appropriate dielectric constants for the lipid tails, inner, and the external leaflet regions, can deliver the same average electrostatic potential distribution as obtained from the MD-generated ensemble of structures. Indeed, this can be attained by using smaller dielectric constant for the tail and inner leaflet regions (mostly hydrophobic) than for the external leaflet region (hydrophilic) and the optimal dielectric constant values are chemotype-specific.
doi:10.1002/jcc.23632
PMCID: PMC4057312  PMID: 24799021
Glycolipids; Phospholipid Bilayers; Poisson-Boltzmann Equation; Multiple Dielectric Constants; Transmembrane Potential; Outer Membrane Remodeling; LPS Phenotype Variation
8.  Between algorithm and model: different Molecular Surface definitions for the Poisson-Boltzmann based electrostatic characterization of biomolecules in solution 
The definition of a molecular surface which is physically sound and computationally efficient is a very interesting and long standing problem in the implicit solvent continuum modeling of biomolecular systems as well as in the molecular graphics field. In this work, two molecular surfaces are evaluated with respect to their suitability for electrostatic computation as alternatives to the widely used Connolly-Richards surface: the blobby surface, an implicit Gaussian atom centered surface, and the skin surface. As figures of merit, we considered surface differentiability and surface area continuity with respect to atom positions, and the agreement with explicit solvent simulations. Geometric analysis seems to privilege the skin to the blobby surface, and points to an unexpected relationship between the non connectedness of the surface, caused by interstices in the solute volume, and the surface area dependence on atomic centers. In order to assess the ability to reproduce explicit solvent results, specific software tools have been developed to enable the use of the skin surface in Poisson-Boltzmann calculations with the DelPhi solver. Results indicate that the skin and Connolly surfaces have a comparable performance from this last point of view.
doi:10.4208/cicp.050711.111111s
PMCID: PMC3601494  PMID: 23519863
Molecular Surface; Connolly Surface; Blobby Surface; Skin Surface; Poisson-Boltzmann
9.  Understanding the Selectivity Mechanism of the Human Asialoglycoprotein Receptor (ASGP-R) toward Gal- and Man-type Ligands for Predicting Interactions with Exogenous Sugars 
A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was set up and validated by checking its ability to predict experimental data, available in the literature, and concerning the selectivity shown by the Carbohydrate Recognition Domain (CRD) of the human asialoglycoprotein receptor (ASGP-R) toward Gal-type ligands. Some required features responsible for the interactions were identified. Subsequently the same protocol was applied to monomer sugar molecules that constitute the building blocks for alginates and ulvans. Such sugar polymers may supply a low-cost source of rare sugars with a potential impact on several industrial applications, from pharmaceutical to fine chemical industry. An example of their applicative exploitation could be given by their use in developing biomaterial with adhesion properties toward hepatocytes, through interaction with the ASGP-R. Such a receptor has been already proposed as a target for exogenous molecules, specifically in the case of hepatocytes, for diagnostic and therapeutic purposes. The DOCK5.2 program was used to search optimal locations of the above ligands of interest into CRD binding site and to roughly estimate interaction energies. Finally, the binding ΔG of theoretical protein-ligand complexes was estimated by using the DelPhi program in which the solvation free energy is accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation. The structure analysis of the obtained complexes and their ΔG values suggest that one of the sugar monomers of interest shows the desired characteristics.
PMCID: PMC3662984
human asialoglycoprotein receptor; molecular docking; DelPhi; natural sugar polymers
10.  Predictions for Proteins, RNAs and DNAs with the Gaussian Dielectric Function Using DelPhiPKa 
Proteins  2015;83(12):2186-2197.
We developed a Poisson-Boltzmann based approach to calculate the PKa values of protein ionizable residues (Glu, Asp, His, Lys and Arg), nucleotides of RNA and single stranded DNA. Two novel features were utilized: the dielectric properties of the macromolecules and water phase were modeled via the smooth Gaussian-based dielectric function in DelPhi and the corresponding electrostatic energies were calculated without defining the molecular surface. We tested the algorithm by calculating PKa values for more than 300 residues from 32 proteins from the PPD dataset and achieved an overall RMSD of 0.77. Particularly, the RMSD of 0.55 was achieved for surface residues, while the RMSD of 1.1 for buried residues. The approach was also found capable of capturing the large PKa shifts of various single point mutations in staphylococcal nuclease (SNase) from PKa -cooperative dataset, resulting in an overall RMSD of 1.6 for this set of pKa’s. Investigations showed that predictions for most of buried mutant residues of SNase could be improved by using higher dielectric constant values. Furthermore, an option to generate different hydrogen positions also improves PKa predictions for buried carboxyl residues. Finally, the PKa calculations on two RNAs demonstrated the capability of this approach for other types of biomolecules.
doi:10.1002/prot.24935
PMCID: PMC4715546  PMID: 26408449
pKa; protein electrostatics; pH-dependent properties of proteins; predicting pKa values of proteins; RNAs and DNAs; Gaussian dielectric function; electrostatic energy calculations
11.  Continuous development of schemes for parallel computing of the electrostatics in biological systems: Implementation in DelPhi 
Journal of computational chemistry  2013;34(22):1949-1960.
Due to the enormous importance of electrostatics in molecular biology, calculating the electrostatic potential and corresponding energies has become a standard computational approach for the study of biomolecules and nano-objects immersed in water and salt phase or other media. However, the electrostatics of large macromolecules and macromolecular complexes, including nano-objects, may not be obtainable via explicit methods and even the standard continuum electrostatics methods may not be applicable due to high computational time and memory requirements. Here, we report further development of the parallelization scheme reported in our previous work (J Comput Chem. 2012 Sep 15; 33(24):1960–6.) to include parallelization of the molecular surface and energy calculations components of the algorithm. The parallelization scheme utilizes different approaches such as space domain parallelization, algorithmic parallelization, multi-threading, and task scheduling, depending on the quantity being calculated. This allows for efficient use of the computing resources of the corresponding computer cluster. The parallelization scheme is implemented in the popular software DelPhi and results in speedup of several folds. As a demonstration of the efficiency and capability of this methodology, the electrostatic potential and electric field distributions are calculated for the bovine mitochondrial supercomplex illustrating their complex topology which cannot be obtained by modeling the supercomplex components alone.
doi:10.1002/jcc.23340
PMCID: PMC3707979  PMID: 23733490
electrostatics; DelPhi; Poisson-Boltzmann equation; parallel computing
12.  The inadvertent disclosure of personal health information through peer-to-peer file sharing programs 
Objective
There has been a consistent concern about the inadvertent disclosure of personal information through peer-to-peer file sharing applications, such as Limewire and Morpheus. Examples of personal health and financial information being exposed have been published. We wanted to estimate the extent to which personal health information (PHI) is being disclosed in this way, and compare that to the extent of disclosure of personal financial information (PFI).
Design
After careful review and approval of our protocol by our institutional research ethics board, files were downloaded from peer-to-peer file sharing networks and manually analyzed for the presence of PHI and PFI. The geographic region of the IP addresses was determined, and classified as either USA or Canada.
Measurement
We estimated the proportion of files that contain personal health and financial information for each region. We also estimated the proportion of search terms that return files with personal health and financial information. We ascertained and discuss the ethical issues related to this study.
Results
Approximately 0.4% of Canadian IP addresses had PHI, as did 0.5% of US IP addresses. There was more disclosure of financial information, at 1.7% of Canadian IP addresses and 4.7% of US IP addresses. An analysis of search terms used in these file sharing networks showed that a small percentage of the terms would return PHI and PFI files (ie, there are people successfully searching for PFI and PHI on the peer-to-peer file sharing networks).
Conclusion
There is a real risk of inadvertent disclosure of PHI through peer-to-peer file sharing networks, although the risk is not as large as for PFI. Anyone keeping PHI on their computers should avoid installing file sharing applications on their computers, or if they have to use such tools, actively manage the risks of inadvertent disclosure of their, their family's, their clients', or patients' PHI.
doi:10.1136/jamia.2009.000232
PMCID: PMC3000774  PMID: 20190057
13.  P2P Watch: Personal Health Information Detection in Peer-to-Peer File-Sharing Networks 
Background
Users of peer-to-peer (P2P) file-sharing networks risk the inadvertent disclosure of personal health information (PHI). In addition to potentially causing harm to the affected individuals, this can heighten the risk of data breaches for health information custodians. Automated PHI detection tools that crawl the P2P networks can identify PHI and alert custodians. While there has been previous work on the detection of personal information in electronic health records, there has been a dearth of research on the automated detection of PHI in heterogeneous user files.
Objective
To build a system that accurately detects PHI in files sent through P2P file-sharing networks. The system, which we call P2P Watch, uses a pipeline of text processing techniques to automatically detect PHI in files exchanged through P2P networks. P2P Watch processes unstructured texts regardless of the file format, document type, and content.
Methods
We developed P2P Watch to extract and analyze PHI in text files exchanged on P2P networks. We labeled texts as PHI if they contained identifiable information about a person (eg, name and date of birth) and specifics of the person’s health (eg, diagnosis, prescriptions, and medical procedures). We evaluated the system’s performance through its efficiency and effectiveness on 3924 files gathered from three P2P networks.
Results
P2P Watch successfully processed 3924 P2P files of unknown content. A manual examination of 1578 randomly selected files marked by the system as non-PHI confirmed that these files indeed did not contain PHI, making the false-negative detection rate equal to zero. Of 57 files marked by the system as PHI, all contained both personally identifiable information and health information: 11 files were PHI disclosures, and 46 files contained organizational materials such as unfilled insurance forms, job applications by medical professionals, and essays.
Conclusions
PHI can be successfully detected in free-form textual files exchanged through P2P networks. Once the files with PHI are detected, affected individuals or data custodians can be alerted to take remedial action.
doi:10.2196/jmir.1898
PMCID: PMC3415260  PMID: 22776692
Privacy; personal health information; natural language processing, text data mining
14.  Electrostatics of ligand binding: parameterization of the generalized Born model and comparison with the Poisson-Boltzmann approach 
The journal of physical chemistry. B  2006;110(18):9304-9313.
An accurate and fast evaluation of the electrostatics in ligand-protein interactions is crucial for computer-aided drug design. The pairwise generalized Born (GB) model, a fast analytical method originally developed for studying solvation of organic molecules, has been widely applied to macromolecular systems, including ligand-protein complexes. Yet, this model involves several empirical scaling parameters, which have been optimized for solvation of organic molecules, peptides and nucleic acids, but not for energetics of ligand binding. Studies have shown that a good solvation energy does not guarantee a correct model of solvent-mediated interactions. Thus in this study, we have used the Poisson-Boltzmann (PB) approach as a reference to optimize the GB model for studies of ligand-protein interactions. Specifically, we have employed the pairwise descreening approximation proposed by Hawkins et al [1] for GB calculations, and DelPhi for PB calculations. The AMBER all-atom force field parameters have been used in this work. Seventeen protein-ligand complexes have been used as a training database, and a set of atomic descreening parameters has been selected with which the pairwise GB model and the PB model yield comparable results on atomic Born radii, the electrostatic component of free energies of ligand binding, and desolvation energies of the ligands and proteins. The energetics of the fifteen test complexes calculated with the GB model using this set of parameters also agrees well with the energetics calculated with the PB method. This is the first time that the GB model is parameterized and thoroughly compared with the PB model for the electrostatics of ligand binding.
doi:10.1021/jp060334w
PMCID: PMC2716126  PMID: 16671749
generalized Born model; ligand-protein binding free energies; solvation
15.  Using DelPhi capabilities to mimic protein’s conformational reorganization with amino acid specific dielectric constants 
Many molecular events are associated with small or large conformational changes occurring in the corresponding proteins. Modeling such changes is a challenge and requires significant amount of computing time. From point of view of electrostatics, these changes can be viewed as a reorganization of local charges and dipoles in response to the changes of the electrostatic field, if the cause is insertion or deletion of a charged amino acid. Here we report a large scale investigation of modeling the changes of the folding energy due to single mutations involving charged group. This allows the changes of the folding energy to be considered mostly electrostatics in origin and to be calculated with DelPhi assigning residue-specific value of the internal dielectric constant of protein. The predicted energy changes are benchmarked against experimentally measured changes of the folding energy on a set of 257 single mutations. The best fit between experimental values and predicted changes is used to find out the effective value of the internal dielectric constant for each type of amino acid. The predicted folding free energy changes with the optimal, amino acid specific, dielectric constants are within RMSD=0.86 kcal/mol from experimentally measured changes.
PMCID: PMC3966310  PMID: 24683422
DelPhi; protein electrostatics; dielectric constant; Poisson-Boltzmann equation; protein flexibility; energy calculations; single point mutations
16.  Evaluation of PHI Hunter in Natural Language Processing Research 
Objectives
We introduce and evaluate a new, easily accessible tool using a common statistical analysis and business analytics software suite, SAS, which can be programmed to remove specific protected health information (PHI) from a text document. Removal of PHI is important because the quantity of text documents used for research with natural language processing (NLP) is increasing. When using existing data for research, an investigator must remove all PHI not needed for the research to comply with human subjects’ right to privacy. This process is similar, but not identical, to de-identification of a given set of documents.
Materials and methods
PHI Hunter removes PHI from free-form text. It is a set of rules to identify and remove patterns in text. PHI Hunter was applied to 473 Department of Veterans Affairs (VA) text documents randomly drawn from a research corpus stored as unstructured text in VA files.
Results
PHI Hunter performed well with PHI in the form of identification numbers such as Social Security numbers, phone numbers, and medical record numbers. The most commonly missed PHI items were names and locations. Incorrect removal of information occurred with text that looked like identification numbers.
Discussion
PHI Hunter fills a niche role that is related to but not equal to the role of de-identification tools. It gives research staff a tool to reasonably increase patient privacy. It performs well for highly sensitive PHI categories that are rarely used in research, but still shows possible areas for improvement. More development for patterns of text and linked demographic tables from electronic health records (EHRs) would improve the program so that more precise identifiable information can be removed.
Conclusions
PHI Hunter is an accessible tool that can flexibly remove PHI not needed for research. If it can be tailored to the specific data set via linked demographic tables, its performance will improve in each new document set.
PMCID: PMC4700871  PMID: 26807078
research ethics; human subjects; protected health information; informatics
17.  Cross-cultural adaptation of the delphi definitions of low back pain prevalence (German DOLBaPP) 
Background
Assessed dimensions of low back pain (LBP) vary in prevalence studies. This may explain the heterogeneity in frequency estimates. To standardize definitions of LBP, an English consensus with 28 experts from 12 countries developed the “Delphi Definitions of Low Back Pain Prevalence” (DOLBaPP). The optimal definition and the shorter minimal definition with the related questionnaires for online, paper, and face-to-face use and telephone surveys are suitable for population-based studies. The definitions have to be adapted to different languages and cultures to provide comparable frequency estimates. The objective was to culturally adapt and pre-test the English definitions and corresponding Delphi DOLBaPP questionnaire forms into German.
Methods
The German DOLBaPP adaptation was conducted using the systematic approach suggested by Beaton et al. A pre-test of the Delphi DOLBaPP optimal paper questionnaire including an additional evaluation form was conducted in a sample of 121 employees (mainly office workers). In order to evaluate the comprehensibility, usability, applicability, and completeness of the adapted questionnaire, response to the questionnaire and 6 closed evaluation questions were analyzed descriptively. Qualitative methods were used for the 3 open questions of the evaluation form.
Results
The cultural adaptation of the DOLBaPP for a German-speaking audience required little linguistic adaptation. Conceptual equivalence was difficult for the expression “low back pain”. The expert committee considered the face validity of the pre-final version of the related Delphi DOLBaPP questionnaires as good. In the pre-test, most participants (95%) needed less than 5 minutes to fill in the optimal Delphi DOLBaPP questionnaire. They were generally positive regarding length, wording, diagram, and composition. All subjects with LBP (n = 61 out of 121 – 50.4%) answered the questions on functional limitation, sciatic pain, frequency and duration of symptoms as well as pain severity.
Conclusion
The results indicate that the cross-cultural German adaptation of the DOLBaPP Definitions and the corresponding questionnaires was successful. The definitions can be used in epidemiological studies to measure the prevalence of LBP. Some critical issues were raised regarding the general features of the Delphi DOLBaPP questionnaires. Future research is needed to evaluate these instruments.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-397) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2474-15-397
PMCID: PMC4258005  PMID: 25425047
Questionnaire; Validation; Low back pain; Pre-test; Cross-cultural adaptation; Prevalence; Site; Symptoms; Duration; Functional limitation
18.  The Integrated Nutrition Pathway for Acute Care (INPAC): Building consensus with a modified Delphi 
Nutrition Journal  2015;14:63.
Background
Malnutrition is commonly underdiagnosed and undertreated in acute care patients. Implementation of current pathways of care is limited, potentially as a result of the perception that they are not feasible with current resources. There is a need for a pathway based on expert consensus, best practice and evidence that addresses this crisis in acute care, while still being feasible for implementation.
Methods
A modified Delphi was used to develop consensus on a new pathway. Extant literature and other resources were reviewed to develop an evidence-informed background document and draft pathway, which were considered at a stakeholder meeting of 24 experts. Two rounds of an on-line Delphi survey were completed (n = 28 and 26 participants respectively). Diverse clinicians from four hospitals participated in focus groups to face validate the draft pathway and a final stakeholder meeting confirmed format changes to make the pathway conceptually clear and easy to follow for end-users. Experts involved in this process were researchers and clinicians from dietetics, medicine and nursing, including management and frontline personnel.
Results
80 % of stakeholders who were invited, participated in the first Delphi survey. The two rounds of the Delphi resulted in consensus for all but two minor components of the Integrated Nutrition Pathway for Acute Care (INPAC). The format of the INPAC was revised based on the input of focus group participants, stakeholders and investigators.
Conclusions
This evidence-informed, consensus based pathway for nutrition care has greater depth and breadth than prior guidelines that were commonly based on systematic reviews. As extant evidence for many best practices is absent, the modified Delphi process has allowed for consensus to be developed based on better practices. Attention to feasibility during development has created a pathway that has greater implementation potential. External validation specifically with practitioner groups promoted a conceptually easy to use format. Test site implementation and evaluation is needed to identify resource requirements and demonstrate process and patient reported outcomes resulting from embedding INPAC into clinical practice.
doi:10.1186/s12937-015-0051-y
PMCID: PMC4473836  PMID: 26089037
Malnutrition; Nutrition screening; SGA; Acute care; Evidence; Care pathway; Delphi survey
19.  Protein Nano-Object Integrator (ProNOI) for generating atomic style objects for molecular modeling 
Background
With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system.
Results
Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style geometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and combined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated, the users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software offers the option to charge the objects with either specified surface or volumetric charge density and to model them with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms can be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The biological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or if a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon (PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot, aptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the barnase-barstar protein complex in its hand.
Conclusions
The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano shapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the atoms in the shapes are assigned according to the user’s preferences allowing various scenarios of modeling. The default output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It can be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz
doi:10.1186/1472-6807-12-31
PMCID: PMC3532097  PMID: 23217202
Biological macromolecules; Electrostatic calculations; Molecular modeling; Nano technology; DelPhi; Poisson-Boltzmann equation
20.  Detection and characterization of small insertion and deletion genetic variants in modern layer chicken genomes 
BMC Genomics  2015;16:562.
Background
Small insertions and deletions (InDels) constitute the second most abundant class of genetic variants and have been found to be associated with many traits and diseases. The present study reports on the detection and characterisation of about 883 K high quality InDels from the whole-genome analysis of several modern layer chicken lines from diverse breeds.
Results
To reduce the error rates seen in InDel detection, this study used the consensus set from two InDel-calling packages: SAMtools and Dindel, as well as stringent post-filtering criteria. By analysing sequence data from 163 chickens from 11 commercial and 5 experimental layer lines, this study detected about 883 K high quality consensus InDels with 93 % validation rate and an average density of 0.78 InDels/kb over the genome. Certain chromosomes, viz, GGAZ, 16, 22 and 25 showed very low densities of InDels whereas the highest rate was observed on GGA6. In spite of the higher recombination rates on microchromosomes, the InDel density on these chromosomes was generally lower relative to macrochromosomes possibly due to their higher gene density. About 43–87 % of the InDels were found to be fixed within each line. The majority of detected InDels (86 %) were 1–5 bases and about 63 % were non-repetitive in nature while the rest were tandem repeats of various motif types. Functional annotation identified 613 frameshift, 465 non-frameshift and 10 stop-gain/loss InDels. Apart from the frameshift and stopgain/loss InDels that are expected to affect the translation of protein sequences and their biological activity, 33 % of the non-frameshift were predicted as evolutionary intolerant with potential impact on protein functions. Moreover, about 2.5 % of the InDels coincided with the most-conserved elements previously mapped on the chicken genome and are likely to define functional elements. InDels potentially affecting protein function were found to be enriched for certain gene-classes e.g. those associated with cell proliferation, chromosome and Golgi organization, spermatogenesis, and muscle contraction.
Conclusions
The large catalogue of InDels presented in this study along with their associated information such as functional annotation, estimated allele frequency, etc. are expected to serve as a rich resource for application in future research and breeding in the chicken.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1711-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1711-1
PMCID: PMC4563830  PMID: 26227840
Dindel; SAMtools; False discovery rate; InDel; Layer chicken; Loss-of-function mutation; Next generation sequencing
21.  Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS) 
BMJ Open  2016;6(12):e011458.
Objectives
The aim of this study was to develop a critical appraisal (CA) tool that addressed study design and reporting quality as well as the risk of bias in cross-sectional studies (CSSs). In addition, the aim was to produce a help document to guide the non-expert user through the tool.
Design
An initial scoping review of the published literature and key epidemiological texts was undertaken prior to the formation of a Delphi panel to establish key components for a CA tool for CSSs. A consensus of 80% was required from the Delphi panel for any component to be included in the final tool.
Results
An initial list of 39 components was identified through examination of existing resources. An international Delphi panel of 18 medical and veterinary experts was established. After 3 rounds of the Delphi process, the Appraisal tool for Cross-Sectional Studies (AXIS tool) was developed by consensus and consisted of 20 components. A detailed explanatory document was also developed with the tool, giving expanded explanation of each question and providing simple interpretations and examples of the epidemiological concepts being examined in each question to aid non-expert users.
Conclusions
CA of the literature is a vital step in evidence synthesis and therefore evidence-based decision-making in a number of different disciplines. The AXIS tool is therefore unique and was developed in a way that it can be used across disciplines to aid the inclusion of CSSs in systematic reviews, guidelines and clinical decision-making.
doi:10.1136/bmjopen-2016-011458
PMCID: PMC5168618  PMID: 27932337
Cross sectional studies; Critical appraisal; Evidence-based Healthcare; Delphi
22.  Treatment patterns, resource use and costs of idiopathic pulmonary fibrosis in Spain – results of a Delphi Panel 
Background
Idiopathic pulmonary fibrosis (IPF) is a form of chronic fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function, with a poor prognosis. The objective of this study was to determine treatment patterns, resource use and costs of managing Spanish patients with IPF.
Methods
A three-round Delphi consensus panel of 15 clinical experts was held between December 2012 and June 2013 using questionnaires to describe the management of patients with IPF. A cost analysis based on Delphi panel estimates was made from the Spanish National Health System (NHS) perspective, including the direct costs of IPF diagnosis and management. Unit costs were applied to Delphi panel estimates of health resource use. Univariate sensitivity analyses were made to evaluate uncertainties in parameters.
Results
The Delphi panel estimated that 20, 60 and 20 % of IPF patients presented with stable disease, slow and rapid disease progression, respectively. The estimated annual cost per patient with stable disease, slow and rapid disease progression was €11,484, €20,978 and €57,759, respectively. This corresponds to a weighted average annual cost of €26,435 with itemized costs of €1,184 (4.5), €7,147 (27.0), €5,950 (22.5), €11,666 (44.1) and €488 (1.9 %) for the diagnosis of IPF, treatment, monitoring, management of acute exacerbations and end-of-life care, respectively. The parameter that varied the annual cost per patient the most was resource use associated with acute exacerbations.
Conclusions
The management of patients with IPF in Spain, especially patients with rapid disease progression, has a high economic impact on the NHS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0168-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12890-016-0168-6
PMCID: PMC4710031  PMID: 26758510
Costs; Delphi technique; Idiopathic pulmonary fibrosis; Spain
23.  PHI-base update: additions to the pathogen–host interaction database 
Nucleic Acids Research  2007;36(Database issue):D572-D576.
The pathogen–host interaction database (PHI-base) is a web-accessible database that catalogues experimentally verified pathogenicity, virulence and effector genes from bacterial, fungal and Oomycete pathogens, which infect human, animal, plant, insect, fish and fungal hosts. Plant endophytes are also included. PHI-base is therefore an invaluable resource for the discovery of genes in medically and agronomically important pathogens, which may be potential targets for chemical intervention. The database is freely accessible to both academic and non-academic users. This publication describes recent additions to the database and both current and future applications. The number of fields that characterize PHI-base entries has almost doubled. Important additional fields deal with new experimental methods, strain information, pathogenicity islands and external references that link the database to external resources, for example, gene ontology terms and Locus IDs. Another important addition is the inclusion of anti-infectives and their target genes that makes it possible to predict the compounds, that may interact with newly identified virulence factors. In parallel, the curation process has been improved and now involves several external experts. On the technical side, several new search tools have been provided and the database is also now distributed in XML format. PHI-base is available at: http://www.phi-base.org/.
doi:10.1093/nar/gkm858
PMCID: PMC2238852  PMID: 17942425
24.  Community Attitudes to the Appropriation of Mobile Phones for Monitoring and Managing Depression, Anxiety, and Stress 
Background
The benefits of self-monitoring on symptom severity, coping, and quality of life have been amply demonstrated. However, paper and pencil self-monitoring can be cumbersome and subject to biases associated with retrospective recall, while computer-based monitoring can be inconvenient in that it relies on users being at their computer at scheduled monitoring times. As a result, nonadherence in self-monitoring is common. Mobile phones offer an alternative. Their take-up has reached saturation point in most developed countries and is increasing in developing countries; they are carried on the person, they are usually turned on, and functionality is continually improving. Currently, however, public conceptions of mobile phones focus on their use as tools for communication and social identity. Community attitudes toward using mobile phones for mental health monitoring and self-management are not known.
Objective
The objective was to explore community attitudes toward the appropriation of mobile phones for mental health monitoring and management.
Methods
We held community consultations in Australia consisting of an online survey (n = 525), focus group discussions (n = 47), and interviews (n = 20).
Results
Respondents used their mobile phones daily and predominantly for communication purposes. Of those who completed the online survey, the majority (399/525 or 76%) reported that they would be interested in using their mobile phone for mental health monitoring and self-management if the service were free. Of the 455 participants who owned a mobile phone or PDA, there were no significant differences between those who expressed interest in the use of mobile phones for this purpose and those who did not by gender (χ21, = 0.98, P = .32, phi = .05), age group (χ24, = 1.95, P = .75, phi = .06), employment status (χ22, = 2.74, P = .25, phi = .08) or marital status (χ24, = 4.62, P = .33, phi = .10). However, the presence of current symptoms of depression, anxiety, or stress affected interest in such a program in that those with symptoms were more interested (χ2 1, = 16.67, P < .001, phi = .19). Reasons given for interest in using a mobile phone program were that it would be convenient, counteract isolation, and help identify triggers to mood states. Reasons given for lack of interest included not liking to use a mobile phone or technology, concerns that it would be too intrusive or that privacy would be lacking, and not seeing the need. Design features considered to be key by participants were enhanced privacy and security functions including user name and password, ease of use, the provision of reminders, and the availability of clear feedback.
Conclusions
Community attitudes toward the appropriation of mobile phones for the monitoring and self-management of depression, anxiety, and stress appear to be positive as long as privacy and security provisions are assured, the program is intuitive and easy to use, and the feedback is clear.
doi:10.2196/jmir.1475
PMCID: PMC3057321  PMID: 21169174
Mobile phones; monitoring; self-help; depression; anxiety; stress; Internet intervention
25.  SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations 
Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/.
doi:10.3390/ijms17040547
PMCID: PMC4849003  PMID: 27077847
missense mutations; energy calculation; binding free energy; MM/PBSA method

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