Neutral Panel Research Articles

Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site

The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.

Restriction Site-Associated DNA Sequencing Reveals Local Adaptation Despite High Levels of Gene Flow in Sardinella lemuru (Bleeker, 1853) Along the Northern Coast of Mindanao, Philippines

Stock identification and delineation are important in the management and conservation of marine resources. These were highlighted as priority research areas for Bali sardinella (Sardinella lemuru) which is among the most commercially important fishery resources in the Philippines. Previous studies have already assessed the stocks of S. lemuru between Northern Mindanao Region (NMR) and Northern Zamboanga Peninsula (NZP), yielding conflicting results. Phenotypic variation suggests distinct stocks between the two regions, while mitochondrial DNA did not detect evidence of genetic differentiation for this high gene flow species. This paper tested the hypothesis of regional structuring using genome-wide single nucleotide polymorphisms (SNPs) acquired through restriction site-associated DNA sequencing (RADseq). We examined patterns of population genomic structure using a full panel of 3,573 loci, which was then partitioned into a neutral panel of 3,348 loci and an outlier panel of 31 loci. Similar inferences were obtained from the full and neutral panels, which were contrary to the inferences from the outlier panel. While the full and neutral panels suggested a panmictic population (global FST ∼ 0, p > 0.05), the outlier panel revealed genetic differentiation between the two regions (global FST = 0.161, p = 0.001; FCT = 0.263, p < 0.05). This indicated that while gene flow is apparent, selective forces due to environmental heterogeneity between the two regions play a role in maintaining adaptive variation. Annotation of the outlier loci returned five genes that were mostly involved in organismal development. Meanwhile, three unannotated loci had allele frequencies that correlated with sea surface temperature. Overall, our results provided support for local adaptation despite high levels of gene flow in S. lemuru. Management therefore should not only focus on demographic parameters (e.g., stock size and catch volume), but also consider the preservation of adaptive variation.

The role and importance of odr in modern business society

ODR procedures involve the filing of electronic documents in which the parties can use encryptionor electronic signatures to protect the integrity of documents and authenticate transactions. Typically, when parties turn to ODR for help,a service provider allows for the appointment of a neutral panel of judgesor panelists. Parties generally prefer structured and clear procedures where the authorisation process is simple and well defined. Institutions such as WIPO, SIAC and ICC have positive track records in resolving online disputes through mediation or other alternative methods of dispute resolution.

Population genomic structure of the gelatinous zooplankton species Mnemiopsis leidyi in its nonindigenous range in the North Sea.

Nonindigenous species pose a major threat for coastal and estuarine ecosystems. Risk management requires genetic information to establish appropriate management units and infer introduction and dispersal routes. We investigated one of the most successful marine invaders, the ctenophore Mnemiopsis leidyi, and used genotyping‐by‐sequencing (GBS) to explore the spatial population structure in its nonindigenous range in the North Sea. We analyzed 140 specimens collected in different environments, including coastal and estuarine areas, and ports along the coast. Single nucleotide polymorphisms (SNPs) were called in approximately 40 k GBS loci. Population structure based on the neutral SNP panel was significant (F ST .02; p < .01), and a distinct genetic cluster was identified in a port along the Belgian coast (Ostend port; pairwise F ST .02–.04; p < .01). Remarkably, no population structure was detected between geographically distant regions in the North Sea (the Southern part of the North Sea vs. the Kattegat/Skagerrak region), which indicates substantial gene flow at this geographical scale and recent population expansion of nonindigenous M. leidyi. Additionally, seven specimens collected at one location in the indigenous range (Chesapeake Bay, USA) were highly differentiated from the North Sea populations (pairwise F ST .36–.39; p < .01). This study demonstrates the utility of GBS to investigate fine‐scale population structure of gelatinous zooplankton species and shows high population connectivity among nonindigenous populations of this recently introduced species in the North Sea.OPEN RESEARCH BADGES This article has earned an Open Data Badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at: The DNA sequences generated for this study are deposited in the NCBI sequence read archive under SRA accession numbers SRR6950721–SRR6950884, and will be made publically available upon publication of this manuscript.

Outlier SNPs detect weak regional structure against a background of genetic homogeneity in the Eastern Rock Lobster, Sagmariasus verreauxi

Genetic differentiation is characteristically weak in marine species making assessments of population connectivity and structure difficult. However, the advent of genomic methods has increased genetic resolution, enabling studies to detect weak, but significant population differentiation within marine species. With an increasing number of studies employing high resolution genome-wide techniques, we are realising that the connectivity of marine populations is often complex and quantifying this complexity can provide an understanding of the processes shaping marine species genetic structure and to inform long-term, sustainable management strategies. This study aims to assess the genetic structure, connectivity, and local adaptation of the Eastern Rock Lobster (Sagmariasus verreauxi), which has a maximum pelagic larval duration of 12 months and inhabits both subtropical and temperate environments. We used 645 neutral and 15 outlier SNPs to genotype lobsters collected from the only two known breeding populations and a third episodic population—encompassing S. verreauxi’s known range. Through examination of the neutral SNP panel, we detected genetic homogeneity across the three regions, which extended across the Tasman Sea encompassing both Australian and New Zealand populations. We discuss differences in neutral genetic signature of S. verreauxi and a closely related, co-distributed rock lobster, Jasus edwardsii, determining a regional pattern of genetic disparity between the species, which have largely similar life histories. Examination of the outlier SNP panel detected weak genetic differentiation between the three regions. Outlier SNPs showed promise in assigning individuals to their sampling origin and may prove useful as a management tool for species exhibiting genetic homogeneity.

Outlier SNPs enable food traceability of the southern rock lobster, Jasus edwardsii

Recent advances in next-generation sequencing have enhanced the resolution of population genetic studies of non-model organisms through increased marker generation and sample throughput. Using double digest restriction site-associated DNA sequencing (ddRADseq), we investigated the population structure of the commercially important southern rock lobster, Jasus edwardsii, in Australia and New Zealand with the aim of identifying a panel of SNP markers that could be used to trace country of origin. Four ddRADseq libraries comprising a total of 88 individuals were sequenced on the Illumina MiSeq platform, and demultiplexed reads were used to create a reference catalog of loci. Individual reads were then mapped to the reference catalog, and variant calling was performed. We have characterized two single-nucleotide polymorphism (SNP) panels comprised in total of 656 SNPs. The first panel contained 535 neutral SNPs and the second, 121 outlier SNPs that were characteristic of being putatively under selection. Both neutral and outlier SNP panels showed significant differentiation between the two countries, with the outlier loci demonstrating much larger F ST values (F ST outlier SNP panel = 0.134, P < 0.0001; F ST neutral SNP panel = 0.022, P < 0.0001). Assignment tests performed with the outlier SNP panel allocated 100 % of the individuals to country of origin, demonstrating the usefulness of these markers for food traceability of J. edwardsii.

Effect of the type of illumination on perceived blackness of automotive finishes

The blackness perception of six black automotive finishes was evaluated under three different illumination conditions: unidirectional illumination, diffuse illumination and light booth condition. The metallic black panels with approximately the same appearance attributes, specular gloss, distinctness of image and orange peel, were selected to minimize the effect of total appearance factors on perceived blackness. Fourteen non-expert observers (5 males and 9 females) assessed the black panels while their normal color vision was examined by the Ishihara test. The pair comparison method was applied to rank the metallic black panels based on their perceived blackness. The results showed that under the diffuse illumination condition, a good correlation was observed between the lightness attribute of metallic black panels and their visual scales, where a decrease of the L* value leads to an increase of perceived blackness. In addition, observers assessed the darkest and the most neutral panel as the blackest sample under the three applied illumination conditions.

CATNAP: a tool to compile, analyze and tally neutralizing antibody panels.

CATNAP (Compile, Analyze and Tally NAb Panels) is a new web server at Los Alamos HIV Database, created to respond to the newest advances in HIV neutralizing antibody research. It is a comprehensive platform focusing on neutralizing antibody potencies in conjunction with viral sequences. CATNAP integrates neutralization and sequence data from published studies, and allows users to analyze that data for each HIV Envelope protein sequence position and each antibody. The tool has multiple data retrieval and analysis options. As input, the user can pick specific antibodies and viruses, choose a panel from a published study, or supply their own data. The output superimposes neutralization panel data, virus epidemiological data, and viral protein sequence alignments on one page, and provides further information and analyses. The user can highlight alignment positions, or select antibody contact residues and view position-specific information from the HIV databases. The tool calculates tallies of amino acids and N-linked glycosylation motifs, counts of antibody-sensitive and -resistant viruses in conjunction with each amino acid or N-glycosylation motif, and performs Fisher's exact test to detect potential positive or negative amino acid associations for the selected antibody. Website name: CATNAP (Compile, Analyze and Tally NAb Panels). Website address: http://hiv.lanl.gov/catnap.

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope.

Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. Many in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth.

Population differentiation determined from putative neutral and divergent adaptive genetic markers in Eulachon (Thaleichthys pacificus, Osmeridae), an anadromous Pacific smelt.

Twelve eulachon (Thaleichthys pacificus, Osmeridae) populations ranging from Cook Inlet, Alaska and along the west coast of North America to the Columbia River were examined by restriction-site-associated DNA (RAD) sequencing to elucidate patterns of neutral and adaptive variation in this high geneflow species. A total of 4104 single-nucleotide polymorphisms (SNPs) were discovered across the genome, with 193 putatively adaptive SNPs as determined by F(ST) outlier tests. Estimates of population structure in eulachon with the putatively adaptive SNPs were similar, but provided greater resolution of stocks compared with a putatively neutral panel of 3911 SNPs or previous estimates with 14 microsatellites. A cline of increasing measures of genetic diversity from south to north was found in the adaptive panel, but not in the neutral markers (SNPs or microsatellites). This may indicate divergent selective pressures in differing freshwater and marine environments between regional eulachon populations and that these adaptive diversity patterns not seen with neutral markers could be a consideration when determining genetic boundaries for conservation purposes. Estimates of effective population size (N(e)) were similar with the neutral SNP panel and microsatellites and may be utilized to monitor population status for eulachon where census sizes are difficult to obtain. Greater differentiation with the panel of putatively adaptive SNPs provided higher individual assignment accuracy compared to the neutral panel or microsatellites for stock identification purposes. This study presents the first SNPs that have been developed for eulachon, and analyses with these markers highlighted the importance of integrating genome-wide neutral and adaptive genetic variation for the applications of conservation and management.

Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance.

For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti-HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV-infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development.

Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains

Delineation of antibody epitopes at the residue level is key to understanding antigen resistance mutations, designing epitope-specific probes for antibody isolation, and developing epitope-based vaccines. Ideally, epitope residues are determined in the context of the atomic-level structure of the antibody-antigen complex, though structure determination may in many cases be impractical. Here we describe an efficient computational method to predict antibody-specific HIV-1 envelope (Env) epitopes at the residue level, based on neutralization panels of diverse viral strains. The method primarily utilizes neutralization potency data over a set of diverse viral strains representing the antigen, and enhanced accuracy could be achieved by incorporating information from the unbound structure of the antigen. The method was evaluated on 19 HIV-1 Env antibodies with neutralization panels comprising 181 diverse viral strains and with available antibody-antigen complex structures. Prediction accuracy was shown to improve significantly over random selection, with an average of greater-than-8-fold enrichment of true positives at the 0.05 false-positive rate level. The method was used to prospectively predict epitope residues for two HIV-1 antibodies, 8ANC131 and 8ANC195, for which we experimentally validated the predictions. The method is inherently applicable to antigens that exhibit sequence diversity, and its accuracy was found to correlate inversely with sequence conservation of the epitope. Together the results show how knowledge inherent to a neutralization panel and unbound antigen structure can be utilized for residue-level prediction of antibody epitopes.

Computational analysis of anti–HIV-1 antibody neutralization panel data to identify potential functional epitope residues

Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti-HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently. A model of an antibody's neutralization IC50 was developed in which each site contributes a term to the logarithm of the modeled IC50. The analysis program attempts to determine the set of rules that minimizes the sum of the residuals between observed and modeled IC50 values. The predictive quality of the identified rules may be assessed in part by whether there is support for rules within individual viral clades. As a test case, we analyzed antibody 8ANC195, an anti-glycoprotein gp120 antibody of unknown specificity. The model for this antibody indicated that several glycosylation sites were critical for neutralization. We evaluated this prediction by measuring neutralization potencies of 8ANC195 against HIV-1 in vitro and in an antibody therapy experiment in humanized mice. These experiments confirmed that 8ANC195 represents a distinct class of glycan-dependent anti-HIV-1 antibody and validated the utility of computational analysis of neutralization panel data.

Clemens’ Retrial Yields Possibility of Jury Nullification

As the lengthy retrial in the Roger Clemens perjury case proceeds, attorneys for both sides have already wrestled with what may be their most critical, yet difficult, task: selection of a neutral jury. Predictably, this case has garnered a slew of media coverage already, and a host of ancillary factors has placed additional significance on this selection process. Finding a neutral panel proved to be an arduous task in this case, particularly with former and prospective jurors publically questioning whether the entire trial is a waste of time and resources, and in light of the nature of the crimes charged against a man of Clemens’ stature. This accumulation of circumstances has propagated an increased likelihood of jury nullification.

A New Design Method of Body-in-White Lightweight Considering NVH Performance

With the development of the auotomobile industry, the body-in-white has to meet the dual requirements of lightweight and NVH performance. This study put forward a new lightweight design method considering NVH performance. An example of lightweighting a non-load-bearing body-in-white was given to illustrate the design flow of this method and certificate the effectiveness and applicability. In order to accurately find out the neutral contribution panels which almost have no influence on the interior acoustic field, a new parameter, the weighted acoustic contribution, was introduced to analyze and evaluate the panel synthetical acoustic contribution to multiple peak frequency at multiple field points. Consequently the whole body-in-white’s weight was reduced by 14.673kg and the interior acoustic field remained basically unchanged.

Research funded by the industry

Bailey and colleagues1 write in this issue of the journal about industry influence on evidence-based surgery. This is a topic that is popular in both the lay and medical media. The discussion is not going to go away. Universities are encouraging industry relationships to help finance academic efforts. Government granting agencies are asking for definitive ties to the corporate world to identify knowledge transfer possibilities that will help get products to market; some grants are based solely on the linkage of commercialization and research. Corporate ties with research are only going to get stronger. This will be a potential problem that we have to monitor. Bhandari and colleagues2 from McMaster University have identified that the odds ratio of a proindustry conclusion in a surgical trial was 5 times greater than that in an industry-sponsored drug trial. I performed a quick search engine verification of Bailey and colleagues’ results. Searching the phrase “medicine industry bias” returns 30 million results in Google. The scientific or medical body of researchers may be lax with analysis of this relationship, as the same search terms only returned 322 results in the PubMed database. Bailey and colleagues actually identified only 190 studies that dealt particularly with bias in surgical studies. Certainly, industry-driven studies have the potential to be biased for many reasons. The design of the studies is heavily warped in favour of a positive result. I have sat on panels that review industry-driven grants and have been able to compare them to researcher-derived grants. With few exceptions, the industry-based grants are poor examples of evidence-based research. In general, industry-based studies are interested in results from a few select surgeons performing a simple procedure or using a device that often is not compared with the gold standard. This is frequently explained as being impossible to perform: for example, autologous bone grafting is too expensive or painful to compare with the new wonder drug. The results are not transferable to the general population, the surgeon users or current surgical practice. But because of their randomized or prospective nature, limited industry-derived studies are considered to have a high level of evidence. We need to be careful with such designations. For example, the bone morphogenetic protein market increased from nothing to an $800-million-a-year niche in less than a decade. This increase occurred on the back of 2 highly quoted human studies that, on further review, may not reflect the data that were initially published. Further research by other groups has never obtained the same results despite hundreds of projects being conducted on the same topic. We need to be vigilant in our interpretation of the literature. Industry-supported research is necessary, otherwise we will have very little funding in the near future. But we need to retain control of more parameters of research and have neutral review panels. The literature should reflect the bias inherent in studies. Finally, journals need to have more information about the design and funding of the studies and report that information to the readers so that the general population can decide for themselves what is meaningful research.

Single‐Nucleotide Polymorphisms (SNPs) under Diversifying Selection Provide Increased Accuracy and Precision in Mixed‐Stock Analyses of Sockeye Salmon from the Copper River, Alaska

AbstractGenetic markers are increasingly being used to ascertain the population of origin of individuals or mixtures of individuals in complex aggregations of Pacific salmon Oncorhynchus spp. Multilocus genotype data from single‐nucleotide polymorphisms (SNPs) are especially useful for admixture analyses. Single‐nucleotide polymorphisms can be discovered in nonmodel organisms with relative ease and can be characterized in the coding and regulatory regions of the genome influenced by selection. Those influenced by diversifying selection may show atypically high levels of differentiation among populations and thus be particularly valuable for genetic stock identification in cases where neutral loci show little difference among populations of interest. We identified four SNP loci from a panel of 42 as candidates for diversifying selection (referred to here as nonneutral SNPs) in sockeye salmon O. nerka from the Copper River and adjacent coastal drainages in south‐central Alaska. We evaluated the information content of the four nonneutral loci for use in genetic stock identification and assessed their ability to improve the accuracy and precision of composition estimates. The average measure of informativeness for assignment (In) for neutral loci was 0.019, and the average In for nonneutral loci was 0.064. A simulation‐based approach indicated that the addition of the nonneutral SNP loci to a neutral marker panel provided significantly higher resolution in the assignment of individuals to their populations of origin than would have been accomplished by adding an equal number of neutral loci. Nonneutral SNP loci improved the ability to identify the origin of individual fish and to estimate the composition of Pacific salmon populations in mixed fisheries.

Identifying Rarer Genetic Variants for Common Complex Diseases: Diseased Versus Neutral Discovery Panels

The power of genetic association studies to identify disease susceptibility alleles fundamentally relies on the variants studied. The standard approach is to determine a set of tagging-SNPs (tSNPs) that capture the majority of genomic variation in regions of interest by exploiting local correlation structures. Typically, tSNPs are selected from neutral discovery panels - collections of individuals comprehensively genotyped across a region. We investigated the implications of discovery panel design on tSNP performance in association studies using realistically-simulated sequence data. We found that discovery panels of 24 sequenced 'neutral' individuals (similar to NIEHS or HapMap ENCODE data) were sufficient to select well-powered tSNPs to identify common susceptibility alleles. For less common alleles (0.01-0.05 frequency) we found neutral panels of this size inadequate, particularly if low-frequency variants were removed prior to tSNP selection; superior tSNPs were found using panels of diseased individuals. Only large neutral panels (200 individuals) matched diseased panel performance in selecting well-powered tSNPs to detect both common and rarer alleles. The 1000 Genomes Project initiative may provide larger neutral panels necessary to identify rarer susceptibility alleles in association studies. In the interim, our results suggest investigators can boost power to detect such alleles by sequencing diseased individuals for tSNP selection.

Comments on NIOSH's Proposed 'B Reader Code of Ethics'

The National Institute for Occupational Safety and Health (NIOSH) has a program to certify doctors as competent to interpret pulmonary X-rays using the International Labour Office (ILO) International Classification of Radiographs (X-rays) of Pneumoconiosis. Doctors so certified are referred to as B Readers. The NIOSH B Reader Program was established to reduce the level of variability among X-ray readers by objectively documenting proficiency in evaluating the characteristics and patterns of images on chest X-rays for occupationally related lung disease. NIOSH currently certifies approximately 400 B Readers. Of this number, approximately 15-25 current and former B Readers have done a majority of the several hundred thousands of B-readings that have been submitted in support of asbestos and silica-related personal injury claims. In several published articles, I have offered the opinion, based upon the evidence I presented, that many of these 15-25 B Readers are not engaged in good faith medical practice but rather provide X-ray readings and diagnoses for litigation purposes that are primarily a function of the millions of dollars a year in income that they receive for their services. Earlier this year, U.S. District Court Judge Janis Jack, presiding over the silica MDL (Docket No. 1553), concluded that lawyers, doctors and screening companies had created a scheme to manufacture [diagnoses] for money. Taking note of the mounting evidence that certain physicians, including NIOSH-certified B Readers, were engaged in improper practice, NIOSH is proposing to adopt Ethical Considerations for B Readers. Federal Register, Vol. 70, No. 221 (Thursday, Nov. 17, 2005/Notices at 69765). I have responded to NIOSH's request for comments on its proposal. In my comments, I briefly review the elements of an entrepreneurial model of nonmalignant asbestos litigation that I more fully describe in my published writings as having come into being in the mid to late 1980s. The core of this entrepreneurial model is the mass screening and the use of B Readers and other physicians to generate medical evidence in support of hundreds of thousands of mostly specious claims. I recommend that NIOSH create an audit process to review the work of high volume B Readers who read X-rays for litigation purposes. Under my proposal, a neutral panel of B Readers will, upon complaint, reread a sample of the B-reads of a litigation doctor to determine whether there is a prima facie case of nonconformance with ILO standards. If the panel concludes that that B Reader has substantially departed from ILO standards, it shall recommend to NIOSH that it withdraw its certification of that Reader. In the event of such recommendation, NIOSH shall notify appropriate state licensing authorities and medical certification boards of that recommendation.

The ethics of health care professionals' opinions for hire

Serving as a forensic consultant or medical expert witness is a professional duty and social responsibility. While objectivity is a hallmark of ethical health care evaluation, conflict arises when medical experts exhibit bias and serve the hiring party's interests instead of the public's. The authors define different types of expert witnesses and examine the means for improving the quality of testimony. They evaluate professional association codes of ethics, health care education, neutral medical experts and the field of bioethics. Incorporating case-based analysis of medical expert testimony in the education of health care professionals may elevate the caliber of testimony. Court-appointed neutral experts may overcome some of the problems inherent in professional and product liability litigation. Neutral bioethicists may play a constructive role in mediating medicolegal disputes. Adopting strong professional association codes of ethics requires the consent of all members, and loss of membership for ethics violations may not be a powerful enough deterrent to biased testimony. Biased testimony contributes to scientifically unfounded liability verdicts. The public ultimately pays for huge monetary settlements via higher costs for all goods and services. Financial incentives in the current professional and product liability system will make it difficult to institute court-appointed neutral expert panels on a widespread basis. Dentists should view themselves as clinicians and evaluators. Rendering expert opinions on forensic matters is an ethical part of dental practice. By doing so with honesty and objectivity, dentists serve as a bridge to justice and fulfill a social responsibility.