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1.  Appreciating the broad clinical features of SMAD4 mutation carriers: a multi-center chart review 
Heterozygous loss-of-function (LOF) SMAD4 mutations are associated with juvenile polyposis syndrome (JP) and hereditary hemorrhagic telangiectasia (HHT). Some carriers exhibit symptoms of both conditions, leading to the name JP-HHT syndrome. Three families have been reported with connective tissue abnormalities. In order to better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n=3), aortic and mitral insufficiency (n=2), aortic dissection (n=1), retinal detachment (n=1), brain aneurysms (n=1), lax skin and joints (n=1). JP-specific findings were almost uniformly present but variable. Ninety-seven percent had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent (15/31) had extensive gastric polyposis. HHT features were documented in 76% including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (AVM) (6/16, 38%), brain AVM (1/26, 4%), pulmonary AVM (9/17, 53%), and intrapulmonary shunting (14/23, 61%). SMAD4 carriers should be managed for JP and HHT, since symptoms of both are likely yet unpredictable. Connective tissue abnormalities are an emerging component of JP-HHT syndrome, and larger studies are needed to understand these manifestations.
doi:10.1038/gim.2014.5
PMCID: PMC4125531  PMID: 24525918
SMAD4; juvenile polyposis; HHT; connective tissue
2.  Frequency of Births Due to Assisted Reproductive Technology (ART) in Prader-Willi Syndrome 
Purpose
Prader-Willi syndrome (PWS) is an imprinting disorder characterized by typical facial, physical and cognitive/behavioral features, resulting from lack of paternally-expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques (ART). This study was designed to determine the association between ART and PWS.
Methods
Data on individuals with PWS were collected from three distinct sources and the proportion of ART-births analyzed.
Results
The proportion of ART-births in the Prader-Willi Syndrome Association [PWSA (USA)], Rare Diseases Clinical Research Network (RDCRN), and University of California, Irvine Medical Center (UCIMC) populations was 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the U.S was 1.0%). Interestingly, 2.4% (45/1,898) of participants were co-twins (eleven born after ART procedures); U.S. twin frequency is 1.6% (p=0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively.
Conclusion
This study found no association between ART and PWS. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the ART group compared to the total PWS participants.
doi:10.1038/gim.2013.97
PMCID: PMC4164429  PMID: 23928912
Prader-Willi syndrome; assisted reproductive techniques; imprinting; twinning; RDCRN
3.  Regulatory changes raise troubling questions for genomic testing 
By 6 October 2014, many laboratories in the United States must begin honoring new individual data access rights created by recent changes to federal privacy and laboratory regulations. These access rights are more expansive than has been widely understood and pose complex challenges for genomic testing laboratories. This article analyzes regulatory texts and guidances to explore which laboratories are affected. It offers the first published analysis of which parts of the vast trove of data generated during next-generation sequencing will be accessible to patients and research subjects. Persons tested at affected laboratories seemingly will have access, upon request, to uninterpreted gene variant information contained in their stored variant call format, binary alignment/map, and FASTQ files. A defect in the regulations will subject some non-CLIA-regulated research laboratories to these new access requirements unless the Department of Health and Human Services takes swift action to avert this apparently unintended consequence. More broadly, all affected laboratories face a long list of daunting operational, business, compliance, and bioethical issues as they adapt to this change and to the Food and Drug Administration’s recently announced plan to publish draft guidance outlining a new oversight framework for lab-developed tests.
doi:10.1038/gim.2014.127
PMCID: PMC4308037  PMID: 25255365
access rights; CLIA; FDA; HIPAA; return of results
4.  [No title available] 
PMCID: PMC4289599  PMID: 24434690
5.  Evidence synthesis and guideline development in genomic medicine: current status and future prospects 
Purpose
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.
Methods
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.”
Results
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.
Conclusion
Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.
doi:10.1038/gim.2014.69
PMCID: PMC4272332  PMID: 24946156
evidence synthesis; genomic medicine; guideline development
6.  Large numbers of individuals required to classify and define risk for rare variants in known cancer risk genes 
Purpose
Up to half of unique genetic variants in genomic evaluations of familial cancer risk will be rare variants of uncertain significance. Classification of rare variants will be an ongoing issue as genomic testing becomes more common.
Methods
We modified standard power calculations to explore sample sizes necessary to classify and estimate relative disease risk for rare variant frequencies (0.001 to 0.00001) and varying relative risk (20 to 1.5) and using population-based and family-based designs focusing on breast and colon cancer. We required 80% power and tolerated a 10% false positive rate, since variants tested will be in known genes with high pretest probability.
Results
Using population-based strategies, hundreds to millions of cases are necessary to classify rare cancer variants. Larger samples are necessary for less frequent and less penetrant variants. Family-based strategies are robust to changes in variant frequency and require between 8 and 1175 individuals, depending on risk.
Conclusion
It is unlikely that most rare missense variants will be classifiable in the near future and accurate relative risk estimates may never be available for very rare variants. This knowledge may alter strategies for communicating information about variants of uncertain significance to patients.
doi:10.1038/gim.2013.187
PMCID: PMC4063879  PMID: 24357849
SAMPLE SIZE CALCULATION; POWER; VARIANT OF UNCERTAIN SIGNIFICANCE; STUDY DESIGN; ODDS RATIO; RELATIVE RISK; VUS; CANCER RISK
7.  Parents' interest in whole-genome sequencing of newborns 
Purpose
The aim of this study was to assess parents' interest in whole-genome sequencing for newborns.
Methods
We conducted a survey of a nationally representative sample of 1,539 parents about their interest in whole-genome sequencing of newborns. Participants were randomly presented with one of two scenarios that differed in the venue of testing: one offered whole-genome sequencing through a state newborn screening program, whereas the other offered whole-genome sequencing in a pediatrician's office.
Results
Overall interest in having future newborns undergo wholegenome sequencing was generally high among parents. If wholegenome sequencing were offered through a state's newborn-screening program, 74% of parents were either definitely or somewhat interested in utilizing this technology. If offered in a pediatrician's office, 70% of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as “very important” in making a decision to have a newborn's whole genome sequenced.
Conclusion
These data may help health departments and children's health-care providers anticipate parents' level of interest in genomic screening for newborns. As whole-genome sequencing is integrated into clinical and public health services, these findings may inform the development of educational strategies and outreach messages for parents.
doi:10.1038/gim.2013.76
PMCID: PMC4164384  PMID: 23743552
newborn screening; parents; whole-genome sequencing
8.  Carrier testing for spinal muscular atrophy 
Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.
doi:10.1097/GIM.0b013e3181ef6079
PMCID: PMC4277882  PMID: 20808230
spinal muscular atrophy; carrier screening; national standards; policy; meeting report
10.  Incidental Findings of Therapeutic Misconception in Biobank-Based Research 
Purpose
This paper explores expressions of therapeutic misconception in a deliberative-engagement project focused on the return of aggregate and individual genetic results from biobank-based research.
Methods
We enrolled 45 self-described African Americans in a deliberative-engagement project to explore their attitudes regarding the return of results from biobank-based research. Four groups of individuals participated in four sessions over two days that included both educational and focus-group components.
Results
Therapeutic misconception was expressed by individuals from both clinics on each day that they met. Three main typological categories of therapeutic misconception were noted: 1) the reasons for consenting to participate in a biobank; 2) the conflation of research with clinical care; and 3) mistrust about the meaning of biomedical research findings.
Discussion
While trust may explain why some research participants express therapeutic misconception, it was also fueled by mistrust (for example, a disbelief that a condition described as untreatable was truly untreatable). We also found that therapeutic misconception is not due solely to research participants' misunderstandings, but is a bidirectional phenomenon that can be exacerbated by researchers. This finding raises questions about how to engage prospective research participants in the long-term goals of biobank-based research without unintentionally overstating possible short-term clinical benefits.
doi:10.1038/gim.2011.50
PMCID: PMC4251740  PMID: 22261760
therapeutic misconception; trust; biobank; return of results; deliberative engagement
11.  Under-utilization of Lynch Syndrome Screening in a Multisite Study of Colorectal Cancer Patients 
Purpose
To examine Lynch Syndrome (LS) screening of metastatic colorectal cancer (mCRC) patients in integrated healthcare delivery organizations.
Methods
We determined the availability of LS screening criteria and actual LS screening in the medical records among 1,188 patients diagnosed with mCRC between 2004–2009 at seven institutions in the Cancer Research Network (CRN).
Results
We found infrequent use of LS screening (41/1188). Family history was available for 937 of the 1188 patients (79%). There was sufficient information to assess LS risk using family history based criteria in 719 of the 937 patients (77%) with family history documentation. In 391 individuals with a family history of a LS-associated cancer, 107 (27%) could not be evaluated due to missing information such as age of cancer onset. Eleven percent of patients who met Bethesda criteria and 25% of individuals who met the Amsterdam II criteria were screened for LS. When screening occurred, it followed recommended guidelines, but no testing method was preferred.
Conclusions
The information required for LS screening decisions is routinely collected but seldom utilized. There is a critical gap between collection of family history and its use to guide LS screening, which may support a case for implementation of universal screening guidelines.
doi:10.1038/gim.2013.43
PMCID: PMC3855589  PMID: 23639899
Lynch Syndrome; genetic testing; metastatic colorectal cancer; family history; hereditary cancer screening
12.  NCI Think Tank Concerning the Identifiability of Biospecimens and “-Omic” Data 
On June 11 and 12, 2012, the National Cancer Institute (NCI) hosted a think tank concerning the identifiability of biospecimens and “omic” Data in order to explore challenges surrounding this complex and multifaceted topic. The think tank brought together forty-six leaders from several fields, including cancer genomics, bioinformatics, human subject protection, patient advocacy, and commercial genetics. The first day involved presentations regarding the state of the science of re-identification; current and proposed regulatory frameworks for assessing identifiability; developments in law, industry and biotechnology; and the expectations of patients and research participants. The second day was spent by think tank participants in small break-out groups designed to address specific sub-topics under the umbrella issue of identifiability, including considerations for the development of best practices for data sharing and consent, and targeted opportunities for further empirical research. We describe the outcomes of this two day meeting, including two complimentary themes that emerged from moderated discussions following the presentations on Day 1, and ideas presented for further empirical research to discern the preferences and concerns of research participants about data sharing and individual identifiability.
doi:10.1038/gim.2013.40
PMCID: PMC4097316  PMID: 23579437
13.  Renal Growth in Isolated Methylmalonic Acidemia (MMA) 
Purpose
We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia (MMA), a group of disorders associated with chronic kidney disease.
Methods
Fifty MMA patients, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared to healthy controls and modeled to other clinical parameters using multiple regression analyses.
Results
Comparisons with age-matched controls showed that renal length in MMA subjects was significantly decreased (p < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate MMA kidney nomograms were: renal length (cm) = 6.79 + 0.22 * age for the controls and 6.80 + 0.09 * age for the MMA cohort (p < 0.001; constant and slope).
Conclusions
Renal length, reflective of kidney growth, significantly decreased in MMA patients over time compared to controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.
doi:10.1038/gim.2013.42
PMCID: PMC4149057  PMID: 23639900
isolated methylmalonic acidemia; renal growth; renal ultrasound; chronic kidney disease; cystatin C; methylmalonyl-CoA mutase; vitamin B12
14.  Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway 
Purpose
The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction.
Methods
Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
Results
All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
Conclusions
NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.
doi:10.1038/gim.2014.22
PMCID: PMC4243708  PMID: 24651605
NGLY1; alacrima; choreoathetosis; seizures; liver disease
15.  Array Comparative Genomic Hybridization (aCGH) Analysis in Patients with Anophthalmia, Microphthalmia and Coloboma 
Purpose
The goal of our study was to determine whether genomic copy number abnormalities (deletions and duplications) affecting genes involved in eye development contribute to the etiology of anophthalmia, microphthalmia and coloboma.
Methods
The affected individuals were tested for deletions and duplications in genomic DNA using 2 million probe (HD2) comparative genomic hybridization arrays (aCGH) from Roche-NimbleGen.
Results
Array analysis of 32 patients detected one case with a deletion encompassing the Renal-coloboma syndrome associated gene PAX2. Non-polymorphic copy number changes were also observed at several candidate chromosomal regions, including 6p12.3, 8q23.1q23.2, 13q31.3, 15q11.2q13.1, 16p13.13 and 20q13.13.
Conclusions
This study identified the first patient with the typical phenotype of the Renal-coloboma syndrome caused by a submicroscopic deletion of the coding region of the PAX2 gene. The finding suggests that PAX2 deletion testing should be performed in addition to gene sequencing as a part of molecular evaluation for the Renal-coloboma syndrome. aCGH testing of 32 affected individual showed that genomic deletions and duplications are not a common cause of non-syndromic anophthalmia, microphthalmia and/or coloboma, but undoubtedly contribute to the etiology of these eye anomalies. aCGH testing therefore represents an important and valuable addition to candidate gene sequencing in research and diagnostics of ocular birth defects.
doi:10.1097/GIM.0b013e318204cfd2
PMCID: PMC4237064  PMID: 21285886
array CGH; deletions; duplications; microphthalmia; anophthalmia; coloboma
16.  Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D 
Purpose
Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot–Marie–Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive CMT disease has not been associated with copy-number variation as a mutational mechanism.
Methods
We performed Agilent 8 × 60K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation.
Results
We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6–8 that caused decreased mRNA expression of NDRG1.
Conclusion
Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.
doi:10.1038/gim.2013.155
PMCID: PMC4224029  PMID: 24136616
autosomal recessive; Charcot–Marie–Tooth disease; CMT4D; CNV; NDRG1
17.  Exploring Pathways to Trust: A Tribal Perspective on Data Sharing 
National Institutes of Health data-sharing policies aim to maximize public benefit derived from genetic studies by increasing research efficiency and the use of a pooled data resource for future studies. While broad access to data may lead to benefits for populations underrepresented in genetic studies, such as indigenous groups, tribes have ownership interest in their data. The Northwest-Alaska Pharmacogenetic Research Network, a partnership involving tribal organizations and universities conducting basic and translational pharmacogenetic research, convened a meeting to discuss the collection, management, and secondary use of research data, and of the processes surrounding access to data stored in federal repositories. This article reports on tribal perspectives that emerged from the dialogue and discusses the implications of tribal government sovereign status on research agreements and data-sharing negotiations. There is strong tribal support for efficient research processes that expedite the benefits from collaborative research, but there is also a need for data sharing procedures that take into account tribal sovereignty and appropriate oversight of research ¬ such as tribally-based research review processes and review of draft manuscripts. We also note specific ways in which accountability could be encouraged by National Institutes of Health as part of the research process.
doi:10.1038/gim.2014.47
PMCID: PMC4224626  PMID: 24830328
genetics; tribal; indigenous; data-sharing; ethics
18.  Experiences and Attitudes of Genome Investigators Regarding Return of Individual Genetic Test Results 
Purpose
Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research.
Methods
We surveyed corresponding authors of genome-wide association studies (GWAS), identified through the National Human Genome Research Institute's Catalog of Published GWAS, to describe the experiences and attitudes of these stakeholders.
Results
Of 357 corresponding authors, 200 (56%) responded. One hundred twenty-six (63%) had been responsible for primary data and sample collection, whereas 74 (37%) had performed secondary analyses. Only 7 (4%) had returned individual results within their index GWAS. Most (69%) believed that return of results to individual participants was warranted under at least some circumstances. Most respondents identified a desire to benefit participants's health (63%) and respect for participants's; desires for information (57%) as major motivations for returning results. Most also identified uncertain clinical utility (76%), the possibility that participants will misunderstand results (74%), the potential for emotional harm (61%), the need to ensure access to trained clinicians (59%), and the potential for loss of confidentiality (51%) as major barriers to return.
Conclusion
Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances.
doi:10.1038/gim.2013.58
PMCID: PMC4143384  PMID: 23639901
20.  Practical challenges in integrating genomic data into the electronic health record 
Genetic testing has had limited impact on routine clinical care. Widespread adoption of electronic health records presents a promising means of disseminating genetic testing into diverse care settings. Practical challenges to integration of genomic data into electronic health records include size and complexity of genetic test results, inadequate use of standards for clinical and genetic data, and limitations in electronic health record capacity to store and analyze genetic data. Related challenges include uncertainty in the interpretation of regulatory requirements for return of results, and privacy concerns specific to genetic testing. Successful integration of genomic data may require significant redesign of existing electronic health record systems.
doi:10.1038/gim.2013.131
PMCID: PMC4201621  PMID: 24071798
clinical decision support systems; electronic health records; genetic testing; genomic medicine
21.  Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers 
Purpose
To evaluate prophylactic salpingo-oophorectomy uptake and timing among BRCA1/2 mutation carriers in a cancer risk assessment program.
Methods
Clinical records of female BRCA1/2 mutation carriers who received cancer genetic counseling between 1996 and 2003 were reviewed to determine the completion and the timing of prophylactic salpingo-oophorectomy. Logistic regression models evaluated associations between subject characteristics and surgery. Survival analysis methods were used to estimate the distribution of time to surgery.
Results
Among 88 women, 70% underwent prophylactic salpingo-oophorectomy. Prophylactic salpingo-oophorectomy was associated with older age, white race, having children, and a family history of ovarian cancer. Many women waited more than 12 months to undergo surgery and some delayed by several years. Younger age and not having children were associated with delays to surgery.
Conclusion
Prophylactic salpingo-ooporectomy is an acceptable risk reduction measure for many BRCA1/2 mutation carriers. Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers.
doi:10.1097/GIM.0b013e318163487d
PMCID: PMC4199586  PMID: 18344704
BRCA1; BRCA2; prophylactic salpingo-oophorectomy
22.  Social and behavioral research in genomic sequencing: approaches from the Clinical Sequencing Exploratory Research Consortium Outcomes and Measures Working Group 
The routine use of genomic sequencing in clinical medicine has the potential to dramatically alter patient care and medical outcomes. To fully understand the psychosocial and behavioral impact of sequencing integration into clinical practice, it is imperative that we identify the factors that influence sequencing-related decision making and patient outcomes. In an effort to develop a collaborative and conceptually grounded approach to studying sequencing adoption, members of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research Consortium formed the Outcomes and Measures Working Group. Here we highlight the priority areas of investigation and psychosocial and behavioral outcomes identified by the Working Group. We also review some of the anticipated challenges to measurement in social and behavioral research related to genomic sequencing; opportunities for instrument development; and the importance of qualitative, quantitative, and mixed-method approaches. This work represents the early, shared efforts of multiple research teams as we strive to understand individuals' experiences with genomic sequencing. The resulting body of knowledge will guide recommendations for the optimal use of sequencing in clinical practice.
doi:10.1038/gim.2014.26
PMCID: PMC4163120  PMID: 24625446
behavior; genome sequencing; measures; outcomes; psychosocial
23.  Integration of Genomics into the Electronic Health Record: Mapping Terra Incognita 
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.
doi:10.1038/gim.2013.102
PMCID: PMC4157459  PMID: 24097178
electronic health record; electronic medical record; genomics; implementation science; clinical decision support; genetics; translational medicine; eMERGE
24.  Description and Pilot Results from a Novel Method for Evaluating Return of Incidental Findings from Next Generation Sequencing Technologies 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1038/gim.2013.37
PMCID: PMC3927794  PMID: 23558254
whole genome sequencing; clinical actionability; population screening; secondary findings; whole exome sequencing
25.  Evaluation of a Decision Aid for Families Considering p53 Genetic Counseling and Testing 
Purpose
Li-Fraumeni syndrome (LFS) is associated with p53 germline mutations, and carriers are at increased risk for multiple primary cancers. We evaluated outcomes following the administration of a video-based decision aid (DA) prior to clinical p53 genetic counseling and testing among persons who had previously participated in cancer genetics research.
Methods
Fifty-seven individuals at risk for a known p53 mutation completed baseline and post-DA measures of psychological outcomes, plus knowledge and attitudes regarding p53 genetic testing. Counseling and testing uptake also was recorded.
Results
At baseline, multivariate analysis showed that greater testing intention was associated with lower decisional conflict (p<0.01). Compared with baseline data, multivariate analyses of post-DA outcomes showed that knowledge about LFS and genetic testing increased and decisional conflict related to testing decreased (p< 0.001). Mean cancer worries scores decreased among all participants (p<0.001), and mean depression scores decreased for males (p<0.05). Thirty-nine (68%) completed pre-test genetic counseling and 23 (40%) subsequently gave a blood sample for clinical genetic testing.
Conclusion
This intervention was useful as an initial outreach and educational method for families considering p53 genetic testing, and may improve knowledge about LFS as well as psychological outcomes.
PMCID: PMC4145599  PMID: 16617243
p53; decision aid; genetic counseling; genetic testing; psychosocial

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