Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
The translational pipeline for genomic medicine has been well defined. However, as with any rapidly changing technology, innovations are difficult to predict leading to the potential to disrupt anticipated translation. Examples of potential disruptors such as laboratory-developed tests, direct-to-consumer testing, and patient-centered research are presented. Awareness of the disruptive nature of innovative approaches is necessary if these innovations are to be incorporated into current practice.
Genomic medicine; Disruption; Innovation; Translational pipeline; Direct-to-consumer; Patient powered research
We describe an “integrated genome-phenome analysis” that combines both genomic sequence data and clinical information for genomic diagnosis. It is novel in that it uses robust diagnostic decision support and combines the clinical differential diagnosis and the genomic variants using a “pertinence” metric. This allows the analysis to be hypothesis-independent, not requiring assumptions about mode of inheritance, number of genes involved, or which clinical findings are most relevant. Using 20 genomic trios with neurologic disease, we find that pertinence scores averaging 99.9% identify the causative variant under conditions in which a genomic trio is analyzed and family-aware variant calling is done. The analysis takes seconds, and pertinence scores can be improved by clinicians adding more findings. The core conclusion is that automated genome-phenome analysis can be accurate, rapid, and efficient. We also conclude that an automated process offers a methodology for quality improvement of many components of genomic analysis.
whole exome sequencing; diagnosis; diagnostic decision support
Transmural migration of a retained surgical sponge causing small bowel obstruction is a rare occurrence. We report a case which demonstrates both the associated foreign body reaction seen on computed tomography months in advance of the onset of symptoms and confirms the subsequent fistulous decompression into the duodenum on both computed tomography and barium meal studies. To the best of the author’s knowledge, a retained surgical swab causing small bowel obstruction has not been previously described with imaging both pre and post transluminal decompression.
Small bowel obstruction; swab; fistula
A girl with early onset severe epilepsy, developmental delay, intellectual disability, visual maturation delays, and feeding problems was without a diagnosis despite an extensive genetic and metabolic evaluation. She initially manifested infantile spasms which responded to high-dose ACTH. Seizures seemed to resolve, but then at age 5, she developed complex partial seizures resistant to antiepileptics that responded to a ketogenic diet. Additional features included visual impairment, hypotonia, reflux, and severe feeding problems requiring a G-tube. She was referred to the Geisinger Health System whole-genome sequencing clinical research program. A variant in the X-linked gene ALG13 (c.320A->G p. 107 N->S) was identified. Four additional girls from three published exome sequencing studies were found to have the identical c.320A>G variant in ALG13. All presented with early onset severe epilepsy and intellectual disability. Three of the five exhibited visual impairment and possible developmental regression. A boy with a variant in ALG13 presented with a severe congenital disorder of glycosylation type Is. Glycosylation studies in the case reported here were normal; none of the other girls reported in the literature have had glycosylation studies. X-inactivation studies have not been done. The N107 residue and the surrounding region – MNNHQ – are highly conserved across species and are found in a presumed functional domain of this glycotransferase superfamily. The consistent clinical presentation of a severe phenotype in girls coupled with identical variants in an X-linked gene strongly suggests a critical position effect. Negative glycosylation studies in one individual suggest the possibility of a new mechanism requiring investigation.
The rate of adherence to regular colonoscopy screening in individuals at increased familial risk of colorectal cancer (CRC) is suboptimal, especially among rural and other geographically underserved populations. Remote interventions may overcome geographic and system-level barriers. We compared the efficacy of a telehealth-based personalized risk assessment and communication intervention with a mailed educational brochure for improving colonoscopy screening among at-risk relatives of patients with CRC.
Eligible individuals age 30 to 74 years who were not up-to-date with risk-appropriate screening and were not candidates for genetic testing were recruited after contacting patients with CRC or their next of kin in five states. Enrollees were randomly assigned as family units to either an active, personalized intervention that incorporated evidence-based risk communication and behavior change techniques, or a mailed educational brochure. The primary outcome was medically verified colonoscopy within 9 months of the intervention.
Of the 481 eligible and randomly assigned at-risk relatives, 79.8% completed the outcome assessments within 9 months; 35.4% of those in the personalized intervention group and 15.7% of those in the comparison group obtained a colonoscopy. In an intent-to-treat analysis, the telehealth group was almost three times as likely to get screened as the low-intensity comparison group (odds ratio, 2.83; 95% CI, 1.87 to 4.28; P < .001). Persons residing in rural areas and those with lower incomes benefitted at the same level as did urban residents.
Remote personalized interventions that consider family history and incorporate evidence-based risk communication and behavior change strategies may promote risk-appropriate screening in close relatives of patients with CRC.
Perchlorate (ClO4−), an oxidizing agent, is a ubiquitous environmental pollutant. Several studies have investigated its thyroid hormone disrupting properties. Its associations with other biological measures are largely unknown. This study, combining 2005–2008 National Health and Nutrition Examination Surveys, investigated associations between urinary perchlorate and biomarkers of iron homeostasis, lipids, blood cell counts, and glucose metabolism. Healthy males (n = 3705), non-pregnant females (n = 2967), and pregnant females (n = 356), aged 12–59 years, were included in the linear regression models, which showed significant positive (+) and negative (−) associations for both males and non-pregnant females with serum uric acid (−), serum iron (−), RBC count (−), blood urea nitrogen (+), and lymphocyte count (+). Other significant associations were observed for either males or non-pregnant females. Among pregnant females, perchlorate was significantly associated with blood urea nitrogen (+) and serum iron (−). These associations may be indicators of perchlorate’s potential effect on several biological systems, which when considered in total, may implicate perturbation of iron homeostasis.
perchlorate; epidemiology; biomarkers; iron homeostasis
With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field.
To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report “Clinical Practice Guidelines We Can Trust.”
The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence.
Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.
evidence synthesis; genomic medicine; guideline development
The Electronic Medical Records and Genomics (eMERGE) Network is a national consortium that is developing methods and best practices for using the electronic health record (EHR) for genomic medicine and research. We conducted a multi-site survey of information resources to support integration of pharmacogenomics into clinical care. This work aimed to: (a) characterize the diversity of information resource implementation strategies among eMERGE institutions; (b) develop a master template containing content topics of important for genomic medicine (as identified by the DISCERN-Genetics tool); and (c) assess the coverage of content topics among information resources developed by eMERGE institutions. Given that a standard implementation does not exist and sites relied on a diversity of information resources, we identified a need for a national effort to efficiently produce sharable genomic medicine resources capable of being accessed from the EHR. We discuss future areas of work to prepare institutions to use infobuttons for distributing standardized genomic content.
Successfully realizing the vision of genomic medicine will require management of large amounts of complex data. The electronic health record (EHR) is destined to play a critical role in the translation of genomic information into clinical care. The papers in this special issue explore the challenges associated with the implementation of genomics in the EHR. The proposed solutions are meant to provide guidance for those responsible for moving genomics into the clinic.
electronic health record; electronic medical record; genomics; implementation science; clinical decision support; genetics; translational medicine; eMERGE
Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few common variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: 1) identify clinically valid genetic variants; 2) decide whether they are actionable and what the action should be; and 3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop.
genomic medicine; clinical actionability; database; electronic health records (EHR); pharmacogenomics; DNA sequencing
To develop, operationalize, and pilot test a transparent, reproducible, and evidence informed method to qualify when to report incidental findings from next generation sequencing technologies.
Using evidence-based principles, we propose a three stage process. Stage I ‘rules out’ incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (Stage III). We used expert opinion to determine the face validity of Stages II and III using three case studies. We evaluated the time and effort for Stages I and II.
For Stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-Antitrypsin Deficiency were all recommended for routine reporting as incidental findings. The method requires less than three days per topic.
We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.
whole genome sequencing; clinical actionability; population screening; secondary findings; whole exome sequencing
Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11–1.24, p = 2.10 × 10−9) and FTO variants and T2D (OR = 1.14, 95% CI = 1.08–1.21, p = 2.34 × 10−6). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07–1.22, p = 3.33 × 10−5); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74–0.91, p = 5.41 × 10−5) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.
PheWAS; genetic association; pleiotropy; Exome chip; FTO; BMI
Particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II enzymes and is essential in protecting against oxidative stress and lung inflammation. We have previously shown that ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to ovalbumin (OVA) in mice. We hypothesized that Nrf2 deficiency in dendritic cells (DC) could enhance the adjuvant potential of UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2 knockout (Nrf2-/-) mice compared with their wild-type (Nrf2+/+) counterparts. Under resting conditions Nrf2-/- DC displayed an intrinsic predilection to a T-helper 2 (Th2)-favoring cytokine profile characterized by low level of IL-12p70 and high level of IL-6 as compared to Nrf2+/+ DC. Adoptive transfer of OVA/UFP-treated Nrf2-/- DC provoked a more severe allergic inflammation in the lung than Nrf2+/+ DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive immune-polarizing cytokine milieu, which we propose may have contributed to the augmented adjuvant effect of UFP on allergic sensitization.
Nrf2; Dendritic cell; Adjuvant; Allergic sensitization; Lung inflammation; Ultrafine particles; IL-12p70; IL-6; T-helper 2
The electronic Medical Records and Genomics (eMERGE) (Phase I) network was established in 2007 to further genomic discovery using biorepositories linked to the electronic health record (EHR). In Phase II, which began in 2011, genomic discovery efforts continue and in addition the network is investigating best practices for implementing genomic medicine, in particular, the return of genomic results in the EHR for use by physicians at point-of-care. To develop strategies for addressing the challenges of implementing genomic medicine in the clinical setting, the eMERGE network is conducting studies that return clinically-relevant genomic results to research participants and their health care providers. These genomic medicine pilot studies include returning individual genetic variants associated with disease susceptibility or drug response, as well as genetic risk scores for common “complex” disorders. Additionally, as part of a network-wide pharmacogenomics-related project, targeted resequencing of 84 pharmacogenes is being performed and select genotypes of pharmacogenetic relevance are being placed in the EHR to guide individualized drug therapy. Individual sites within the eMERGE network are exploring mechanisms to address incidental findings generated by resequencing of the 84 pharmacogenes. In this paper, we describe studies being conducted within the eMERGE network to develop best practices for integrating genomic findings into the EHR, and the challenges associated with such work.
genomics; electronic health records; incidental findings; implementation; genetic counseling; next generation sequencing; pharmacogenetics
There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.
A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.
The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
Background and objectives
Worry is predominantly a verbal-linguistic process with relatively little imagery. This study investigated whether the verbal nature of worry contributes to the maintenance of worry by enhancing attention to threat. It was hypothesised that verbal worry would lead to greater attentional bias to threat than imagery-based worry.
Fifty high-worriers were randomly assigned to one of two groups, one in which they were instructed to worry in a verbal way and one in which they worried in an imagery-based way, before completing a dot probe task as a measure of attention to threat-related words.
Those who worried in verbal form demonstrated greater attentional bias to threat than did those who worried in imagery-based form. These findings could not be accounted for by group differences in personal relevance of or distress associated with worry topics, state mood following worry, levels of the relatedness of participants' worries to stimuli on the dot probe task, trait anxiety, general propensity to worry, nor adherence to the worry training.
The present study only included word stimuli in the dot probe task; inclusion of images would allow for firmly rejecting the hypothesis that the attention effects observed following verbal worry were merely a result of priming verbal threat representations. Also, future studies could include a further control group that does not engage in any form of worry to ascertain that verbal worry increased attentional bias rather than imagery decreasing pre-existing attentional bias.
Possible mechanisms underlying this effect of verbal worry on attention to threat are discussed, together with clinical implications of the current findings.
•Worry is predominantly a verbal-linguistic process with relatively little imagery.•High-worriers worried in verbal or imagery form before an emotional dot probe task.•Verbal worry is associated with attentional bias for threat words.•Imagery-based worry is not associated with an attentional bias for threat words.•The verbal nature of worry has a causal role in its maintenance.
Worry; Attention; Imagery; Verbal-linguistic processing; Dot probe
Whole genome sequencing (WGS) is being used for evaluation of individuals with undiagnosed disease of suspected genetic origin. Implementing WGS into clinical practice will place an increased burden upon care teams with regard to pre-test patient education and counseling about results. To quantitate the time needed for appropriate pre-test evaluation of participants in WGS testing, we documented the time spent by our clinical research group on various activities related to program preparation, participant screening, and consent prior to WGS. Participants were children or young adults with autism, intellectual or developmental disability, and/or congenital anomalies, who have remained undiagnosed despite previous evaluation, and their biologic parents. Results showed that significant time was spent in securing allocation of clinical research space to counsel participants and families, and in acquisition and review of participant’s medical records. Pre-enrollment chart review identified two individuals with existing diagnoses resulting in savings of $30,000 for the genome sequencing alone, as well as saving hours of personnel time for genome interpretation and communication of WGS results. New WGS programs should plan for costs associated with additional pre-test administrative planning and patient evaluation time that will be required to provide high quality care.
Electronic supplementary material
The online version of this article (doi:10.1007/s10897-014-9697-4) contains supplementary material, which is available to authorized users.
Whole genome sequencing; Time study; Electronic health record; Genetic counseling; Intellectual disability
The inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.
clinical decision support, electronic health records; ethical, legal, and social implications; genomics; personalized medicine
Next Generation Sequencing studies generate a large quantity of genetic data in a relatively cost and time efficient manner and provide an unprecedented opportunity to identify candidate causative variants that lead to disease phenotypes. A challenge to these studies is the generation of sequencing artifacts by current technologies. To identify and characterize the properties that distinguish false positive variants from true variants, we sequenced a child and both parents (one trio) using DNA isolated from three sources (blood, buccal cells, and saliva). The trio strategy allowed us to identify variants in the proband that could not have been inherited from the parents (Mendelian errors) and would most likely indicate sequencing artifacts. Quality control measurements were examined and three measurements were found to identify the greatest number of Mendelian errors. These included read depth, genotype quality score, and alternate allele ratio. Filtering the variants on these measurements removed ~95% of the Mendelian errors while retaining 80% of the called variants. These filters were applied independently. After filtering, the concordance between identical samples isolated from different sources was 99.99% as compared to 87% before filtering. This high concordance suggests that different sources of DNA can be used in trio studies without affecting the ability to identify causative polymorphisms. To facilitate analysis of next generation sequencing data, we developed the Cincinnati Analytical Suite for Sequencing Informatics (CASSI) to store sequencing files, metadata (eg. relatedness information), file versioning, data filtering, variant annotation, and identify candidate causative polymorphisms that follow either de novo, rare recessive homozygous or compound heterozygous inheritance models. We conclude the data cleaning process improves the signal to noise ratio in terms of variants and facilitates the identification of candidate disease causative polymorphisms.
whole exome sequencing; variant filtering; next-generation sequencing; disease causative polymorphisms; Mendelian errors; Mendel errors; CASSI
Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies. We add to this evidence-based recommendations that are specific to issues at the intersection of genomics and the electronic health record. We describe stakeholder engagement strategies employed by the Electronic Medical Records and Genomics Network, a national consortium of US research institutions funded by the National Human Genome Research Institute to develop, disseminate, and apply approaches that combine genomic and electronic health record data. Through select examples drawn from sites of the Electronic Medical Records and Genomics Network, we illustrate a continuum of engagement strategies to inform genomic integration into commercial and homegrown electronic health records across a range of health-care settings. We frame engagement as activities to consult, involve, and partner with key stakeholder groups throughout specific phases of health information technology implementation. Our aim is to provide insights into engagement strategies to guide genomic integration based on our unique network experiences and lessons learned within the broader context of implementation research in biomedical informatics. On the basis of our collective experience, we describe key stakeholder practices, challenges, and considerations for successful genomic integration to support personalized medicine.
electronic health records; genomics; health information technology; personalized medicine; stakeholder engagement; translational medical research