Polygenic score accuracy in ancient samples: Quantifying the effects of allelic turnover.

Polygenic scores link the genotypes of ancient individuals to their phenotypes, which are often unobservable, offering a tantalizing opportunity to reconstruct complex trait evolution. In practice, however, interpretation of ancient polygenic scores is subject to numerous assumptions. For one, the genome-wide association (GWA) studies from which polygenic scores are derived, can only estimate effect sizes for loci segregating in contemporary populations. Therefore, a GWA study may not correctly identify all loci relevant to trait variation in the ancient population. In addition, the frequencies of trait-associated loci may have changed in the intervening years. Here, we devise a theoretical framework to quantify the effect of this allelic turnover on the statistical properties of polygenic scores as functions of population genetic dynamics, trait architecture, power to detect significant loci, and the age of the ancient sample. We model the allele frequencies of loci underlying trait variation using the Wright-Fisher diffusion, and employ the spectral representation of its transition density to find analytical expressions for several error metrics, including the expected sample correlation between the polygenic scores of ancient individuals and their true phenotypes, referred to as polygenic score accuracy. Our theory also applies to a two-population scenario and demonstrates that allelic turnover alone may explain a substantial percentage of the reduced accuracy observed in cross-population predictions, akin to those performed in human genetics. Finally, we use simulations to explore the effects of recent directional selection, a bias-inducing process, on the statistics of interest. We find that even in the presence of bias, weak selection induces minimal deviations from our neutral expectations for the decay of polygenic score accuracy. By quantifying the limitations of polygenic scores in an explicit evolutionary context, our work lays the foundation for the development of more sophisticated statistical procedures to analyze both temporally and geographically resolved polygenic scores.

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.

There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

Tyroviruses are a new group of temperate phages that infect Bacillus species in soil environments worldwide.

BACKGROUND: Bacteriophages are widely considered to be highly abundant and genetically diverse, with their role in the evolution and virulence of many pathogens becoming increasingly clear. Less attention has been paid on phages preying on Bacillus, despite the potential for some of its members, such as Bacillus anthracis, to cause serious human disease. RESULTS: We have isolated five phages infecting the causative agent of anthrax, Bacillus anthracis. Using modern phylogenetic approaches we place these five new Bacillus phages, as well as 21 similar phage genomes retrieved from publicly available databases and metagenomic datasets into the Tyrovirus group, a newly proposed group named so due to the conservation of three distinct tyrosine recombinases. Genomic analysis of these large phages (~ 160-170 kb) reveals their DNA packaging mechanism and genomic features contributing to virion morphogenesis, host cell lysis and phage DNA replication processes. Analysis of the three tyrosine recombinases suggest Tyroviruses undergo a prophage lifecycle that may involve both host integration and plasmid stages. Further we show that Tyroviruses rely on divergent invasion mechanisms, with a subset requiring host S-layer for infection. CONCLUSIONS: Ultimately, we expand upon our understanding on the classification, phylogeny, and genomic organisation of a new and substantial phage group that prey on critically relevant Bacillus species. In an era characterised by a rapidly evolving landscape of phage genomics the deposition of future Tyroviruses will allow the further unravelling of the global spread and evolutionary history of these Bacillus phages.

Telehealth Utilization Among Surgical Oncology Patients at a Large Academic Cancer Center.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic increased the use of telehealth within medicine. Data on sociodemographic and clinical characteristics associated with telehealth utilization among cancer surgical patients have not been well-defined. METHODS: Cancer patients who had a surgical oncology visit at the James Cancer Hospital in March 2020-May 2021 were included. Patient demographic and clinical characteristics were recorded; access to modern information technology was measured using the Digital Divide Index (DDI). A logistic regression model was used to assess odds of receiving a telehealth. RESULTS: Among 2942 patients, median DDI was 18.2 (interquartile range 17.4-22.1). Patients were most often insured through managed care (n = 1459, 49.6%), followed by Medicare (n = 1109, 37.7%) and Medicaid (n = 267, 9.1%). Overall, 722 patients (24.5%) received at least one telehealth visit over the study period. On multivariable analysis, age (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80-0.98 per 10-year increase), sex (male vs. female: OR 1.83, 95% CI 1.45-2.32), cancer type (pancreatic vs. breast: OR 9.19, 95% CI 6.38-13.23; colorectal vs. breast: OR 5.31, 95% CI 3.71-7.58), insurance type (Medicare vs. Medicaid: OR 1.58, 95% CI 1.04-2.41) and county of residence (distant vs. neighboring: OR 1.33, 95% CI 1.06-1.66) were associated with increased odds of receiving a telehealth visit. Patients from high DDI counties were not less likely to receive telehealth visits versus patients from low DDI counties (OR 1.15, 95% CI 0.85-1.57). CONCLUSIONS: Several patient sociodemographic and clinical characteristics had an impact on the likelihood of receiving a telehealth visit versus an in-person visit, suggesting that telehealth may not be equally accessible to all surgical oncology patients.

Implications of intensive care unit admissions among medicare beneficiaries following resection of pancreatic cancer.

BACKGROUND: Intensive care unit (ICU) use has increased among patients with cancer. We sought to define factors associated with ICU admissions among patients with pancreatic cancer and characterize trends in mortality among hospital survivors. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database was used to identify patients with pancreatic cancer who underwent resection. Multivariable analyses were conducted to identify factors associated with ICU admission and mortality among hospital survivors. RESULTS: Among 6422 Medicare beneficiaries who underwent resection of pancreatic cancer, 2386 (37.1%) had an ICU admission. Patients with ICU admissions were more likely to be younger (10-year increase odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.77-0.89), male (OR: 1.17, 95% CI 1.05-1.30) and undergo resection at a teaching hospital (OR: 1.19, 95% CI: 1.05-1.36). While the majority of patients survived to hospital discharge (n = 2106; 88.3%), a majority of patients (n = 1296; 54.3%) died within 6 months. Among patients who had subsequent ICU admissions, 1- and 5-year survival was only 31.8% and 11.0%, respectively. CONCLUSIONS: Over one-third of patients with pancreatic cancer had an ICU admission. While most patients survived hospitalization, more than one-half of patients died within 6 months of discharge and two-thirds died within 1 year. These data should serve to guide patient-provider discussions around prognosis relative to ICU utilization.

Sex speeds adaptation by altering the dynamics of molecular evolution.

Sex and recombination are pervasive throughout nature despite their substantial costs. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation. Theory has proposed several distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect) or by separating them from deleterious load (the ruby in the rubbish effect). Previous experiments confirm that sex can increase the rate of adaptation, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here we present the first, to our knowledge, comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual Saccharomyces cerevisiae populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations.

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

End-of-Life Hospice Use and Medicare Expenditures Among Patients Dying of Hepatocellular Carcinoma.

BACKGROUND: The increasing incidence of hepatocellular carcinoma (HCC) coupled with rising health care costs contributes to high end-of-life expenditures. The current study aimed to characterize health care expenditures and hospice use among patients with HCC using a large, national database. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database was used to identify patients with HCC. Logistic regression was used to identify factors associated with overall hospice use and end-of-life expenditures among individuals who died of HCC. RESULTS: Among 14,369 Medicare beneficiaries with HCC, 8069 (63.7 %) used hospice. Racial/ethnic minority patients were less likely to use hospice services during the last year of life than white patients (no hospice: n = 2034 [44.3 %] vs. hospice: n = 2513 [31.1 %]). Social vulnerability also had an impact on the likelihood of patients using hospice services; in particular, the probability of hospice use among patients declined as social vulnerability increased (P < 0.05). Hospice use was associated with an approximate $10,000 decrease in inpatient expenditures (hospice: US$7900 [IQR, US$0-26,600] vs. no hospice: US$18,000 [IQR $400-49,100]; P < 0.001) and $1300 decrease in outpatient expenditures (hospice: US$900 [IQR, US$0-4500] vs. non-hospice: US$2200 [IQR, US$200-7900; P < 0.001) compared with individuals who did not use hospice. CONCLUSIONS: Minority patients and individuals residing in high-vulnerability areas were less likely to use hospice. Patients who used hospice at the end of life had a reduction in inpatient and outpatient Medicare claims. Patients with HCC in need of hospice services should be ensured timely referral regardless of race/ethnicity or social vulnerability.

Do Religious/Spiritual Preferences and Needs of Cancer Patients Vary Based on Clinical- and Treatment-Level Factors?

BACKGROUND: The objective of this study is to characterize the religion and spiritual (R&S) needs of patients who undergo cancer-directed surgery. In addition, we seek to examine how R&S needs vary based on R&S identity and clinical and surgical treatment characteristics. PATIENTS AND METHODS: A cross-sectional survey was administered to potential participants who were recruited through outpatient clinics and online. Respondent desires for R&S resources and engagement with the healthcare team  around R&S topics were assessed. RESULTS: Among 383 potential participants who were identified, 236 respondents were included in the analytic cohort. Mean age was 58.8 (SD 12.10) years, and most participants were female (75.8%) and White/Caucasian (94.1%). The majority (78.4%) identified as currently cancer free. Commonly treated malignancies included breast (43.2%), male reproductive (8.9%), skin (8.5%), and gastrointestinal (GI) (7.2%). Two-thirds of the respondents indicated a desire to have R&S incorporated into their cancer treatment (63.3%). Patients who identified as highly/moderately religious reported wanting R&S more often (highly religious: 95.2% versus moderately religious: 71.4% vs. nonreligious but spiritual: 4.5%). On multivariable analysis, patients who believed their health would improve in the future were more likely to report wanting R&S service (OR 2.2, 95% CI 1.0-4.7) as well as wanting to engage their healthcare providers on R&S topics (OR 2.4, 95% CI 1.2-4.7). In contrast, perception of current or future health status was not associated with patient desire for the actual surgeon/doctor him/herself to be involved in R&S activities (OR 1.83, 95% CI 0.97-3.45). CONCLUSIONS: Two-thirds of patients undergoing cancer-directed surgery expressed a desire to have R&S incorporated into their cancer treatment. Incorporating R&S into cancer treatment can help a subset of patients throughout their cancer experience.

Adaptive evolution of genomically recoded Escherichia coli.

Efforts are underway to construct several recoded genomes anticipated to exhibit multivirus resistance, enhanced nonstandard amino acid (nsAA) incorporation, and capability for synthetic biocontainment. Although our laboratory pioneered the first genomically recoded organism (Escherichia coli strain C321.∆A), its fitness is far lower than that of its nonrecoded ancestor, particularly in defined media. This fitness deficit severely limits its utility for nsAA-linked applications requiring defined media, such as live cell imaging, metabolic engineering, and industrial-scale protein production. Here, we report adaptive evolution of C321.∆A for more than 1,000 generations in independent replicate populations grown in glucose minimal media. Evolved recoded populations significantly exceeded the growth rates of both the ancestral C321.∆A and nonrecoded strains. We used next-generation sequencing to identify genes mutated in multiple independent populations, and we reconstructed individual alleles in ancestral strains via multiplex automatable genome engineering (MAGE) to quantify their effects on fitness. Several selective mutations occurred only in recoded evolved populations, some of which are associated with altering the translation apparatus in response to recoding, whereas others are not apparently associated with recoding, but instead correct for off-target mutations that occurred during initial genome engineering. This report demonstrates that laboratory evolution can be applied after engineering of recoded genomes to streamline fitness recovery compared with application of additional targeted engineering strategies that may introduce further unintended mutations. In doing so, we provide the most comprehensive insight to date into the physiology of the commonly used C321.∆A strain.

The religious/spiritual beliefs and needs of cancer survivors who underwent cancer-directed surgery.

OBJECTIVE: We sought to characterize patients' preferences for the role of religious and spiritual (R&S) beliefs and practices during cancer treatment and describe the R&S resources desired by patients during the perioperative period. METHOD: A cross-sectional survey was administered to individuals who underwent cancer-directed surgery. Data on demographics and R&S beliefs/preferences were collected and analyzed. RESULTS: Among 236 participants, average age was 58.8 (SD = 12.10) years; the majority were female (76.2%), white (94.1%), had a significant other or spouse (60.2%), and were breast cancer survivors (43.6%). Overall, more than one-half (55.9%) of individuals identified themselves as being religious, while others identified as only spiritual (27.9%) or neither (16.2%). Patients who identified as religious wanted R&S integrated into their care more often than patients who were only spiritual or neither (p < 0.001). Nearly half of participants (49.6%) wanted R&S resources when admitted to the hospital including the opportunity to speak with an R&S leader (e.g., rabbi; 72.1%), R&S texts (64.0%), and journaling materials (54.1%). Irrespective of R&S identification, 68.0% of patients did not want their physician to engage with them about R&S topics. SIGNIFICANCE OF RESULTS: Access to R&S resources is important during cancer treatment, and incorporating R&S into cancer care may be especially important to patients that identify as religious. R&S needs should be addressed as part of the cancer care plan.

The community compositions of three nitrogen removal wastewater treatment plants of different configurations in Victoria, Australia, over a 12-month operational period.

Amplicon sequence fingerprinting of communities in activated sludge systems have provided data revealing the true level of their microbial biodiversity and led to suggestions of which intrinsic and extrinsic parameters might affect the dynamics of community assemblage. Most studies have been performed in China and Denmark, and comparatively little information is available for plants in other countries. This study looked at how the communities of three plants in Victoria, Australia, treating domestic sewage changed with season. All were designed to remove nitrogen microbiologically. They were all located close together to minimise any influence that climate and demographics might have on their operation, and samples were taken at weekly intervals for 12 months. 16S rRNA amplicon sequencing revealed that each plant community was distinctively different to the others and changed over the 12-month sampling period. Many of the factors suggested in other similar studies to be important in determining community composition in activated sludge systems could not explain the changes noted here. The most likely influential factors were considered to be temperature and influent composition reflecting changes in dietary intake by the populations served by each plant, since in all three, the most noticeable changes corresponded to seasonal shifts. KEY POINTS: • Monitoring microbial communities in 3 wastewater treatment plants removing nitrogen • Temperature is the most influential factor in dynamic changes in community composition.

Pervasive genetic hitchhiking and clonal interference in forty evolving yeast populations.

The dynamics of adaptation determine which mutations fix in a population, and hence how reproducible evolution will be. This is central to understanding the spectra of mutations recovered in the evolution of antibiotic resistance, the response of pathogens to immune selection, and the dynamics of cancer progression. In laboratory evolution experiments, demonstrably beneficial mutations are found repeatedly, but are often accompanied by other mutations with no obvious benefit. Here we use whole-genome whole-population sequencing to examine the dynamics of genome sequence evolution at high temporal resolution in 40 replicate Saccharomyces cerevisiae populations growing in rich medium for 1,000 generations. We find pervasive genetic hitchhiking: multiple mutations arise and move synchronously through the population as mutational 'cohorts'. Multiple clonal cohorts are often present simultaneously, competing with each other in the same population. Our results show that patterns of sequence evolution are driven by a balance between these chance effects of hitchhiking and interference, which increase stochastic variation in evolutionary outcomes, and the deterministic action of selection on individual mutations, which favours parallel evolutionary solutions in replicate populations.

Simultaneous Identification of Campylobacter jejuni, Campylobacter coli, and Campylobacter lari with SmartCycler-Based Multiplex Quantitative Polymerase Chain Reaction.

BACKGROUND: Consumption of Campylobacter contaminated food or water is a leading cause of human acute gastroenteritis. Campylobacter jejuni, Campylobacter coli, and Campylobacter lari account for over 95% of total Campylobacter infections. A multiplex quantitative polymerase chain reaction (qPCR) for simultaneous identification of C. jejuni, C. coli, and C. lari was developed for use with the SmartCycler II system. MATERIALS AND METHODS: We evaluated and combined previously described primers and probes for Campylobacter detection, designed a new internal amplification control, and optimized the multiplex qPCR for the detection of C. jejuni, C. coli, and C. lari. RESULTS: This method was 100% specific when tested against a panel of 32 target Campylobacter strains and 31 non-Campylobacter reference strains. Furthermore, there was no cross-reactivity with seven strains from four nontarget Campylobacter species. The amplification efficiency of each target in this multiplex qPCR was over 90%, and each coefficient of linearity was greater than 0.99. With artificially mixed genomic DNA, this method detected as few as two, three, and two genome copies of C. jejuni, C. coli, and C. lari, respectively. This method was also able to detect these three Campylobacter species in artificially contaminated milk with a sensitivity of five spiked cells of each target per reaction. CONCLUSION: The three Campylobacter targets were simultaneously identified using artificially mixed genomic DNA and spiked raw milk. This SmartCycler-based multiplex qPCR is a rapid, specific, and sensitive method to identify C. jejuni, C. coli, and C. lari.

Gene Expression Evolves under a House-of-Cards Model of Stabilizing Selection.

Divergence in gene regulation is hypothesized to underlie much of phenotypic evolution, but the role of natural selection in shaping the molecular phenotype of gene expression continues to be debated. To resolve the mode of gene expression, evolution requires accessible theoretical predictions for the effect of selection over long timescales. Evolutionary quantitative genetic models of phenotypic evolution can provide such predictions, yet those predictions depend on the underlying hypotheses about the distributions of mutational and selective effects that are notoriously difficult to disentangle. Here, we draw on diverse genomic data sets including expression profiles of natural genetic variation and mutation accumulation lines, empirical estimates of genomic mutation rates, and inferences of genetic architecture to differentiate contrasting hypotheses for the roles of stabilizing selection and mutation in shaping natural expression variation. Our analysis suggests that gene expression evolves in a domain of phenotype space well fit by the House-of-Cards (HC) model. Although the strength of selection inferred is sensitive to the number of loci controlling gene expression, the model is not. The consistency of these results across evolutionary time from budding yeast through fruit fly implies that this model is general and that mutational effects on gene expression are relatively large. Empirical estimates of the genetic architecture of gene expression traits imply that selection provides modest constraints on gene expression levels for most genes, but that the potential for regulatory evolution is high. Our prediction using data from laboratory environments should encourage the collection of additional data sets allowing for more nuanced parameterizations of HC models for gene expression.

Estimation of 3D shape from image orientations.

One of the main functions of vision is to estimate the 3D shape of objects in our environment. Many different visual cues, such as stereopsis, motion parallax, and shading, are thought to be involved. One important cue that remains poorly understood comes from surface texture markings. When a textured surface is slanted in 3D relative to the observer, the surface patterns appear compressed in the retinal image, providing potentially important information about 3D shape. What is not known, however, is how the brain actually measures this information from the retinal image. Here, we explain how the key information could be extracted by populations of cells tuned to different orientations and spatial frequencies, like those found in the primary visual cortex. To test this theory, we created stimuli that selectively stimulate such cell populations, by "smearing" (filtering) images of 2D random noise into specific oriented patterns. We find that the resulting patterns appear vividly 3D, and that increasing the strength of the orientation signals progressively increases the sense of 3D shape, even though the filtering we apply is physically inconsistent with what would occur with a real object. This finding suggests we have isolated key mechanisms used by the brain to estimate shape from texture. Crucially, we also find that adapting the visual system's orientation detectors to orthogonal patterns causes unoriented random noise to look like a specific 3D shape. Together these findings demonstrate a crucial role of orientation detectors in the perception of 3D shape.

Developing a competency framework for U.S. state food and feed testing laboratory personnel.

A competency-based training curriculum framework for U.S. state food and feed testing laboratories personnel is being developed by the International Food Protection Training Institute (IFPTI) and three partners. The framework will help laboratories catalog existing training courses/modules, identify training gaps, inform training curricula, and create career-spanning professional development learning paths, ensuring consistent performance expectations and increasing confidence in shared test results. Ultimately, the framework will aid laboratories in meeting the requirements of ISO/IEC 17025 (2005) international accreditation and the U.S. Food Safety Modernization Act (U.S. Public Law 111-353). In collaboration with the Association of Food and Drug Officials, the Association of Public Health Laboratories, and the Association of American Feed Control Officials, IFPTI is carrying out the project in two phases. In 2013, an expert panel of seven subject matter experts developed competency and curriculum frameworks for five professional levels (entry, mid-level, expert, supervisor/manager, and senior administration) across four competency domains (technical, communication, programmatic, and leadership) including approximately 80 competencies. In 2014 the expert panel will elicit feedback from peers and finalize the framework.