A tiered-layered-staged model for informed consent in personal genome testing

In recent years, developments in genomics technologies have led to the rise of commercial personal genome testing (PGT): broad genome-wide testing for multiple diseases simultaneously. While some commercial providers require physicians to order a personal genome test, others can be accessed directly. All providers advertise directly to consumers and offer genetic risk information about dozens of diseases in one single purchase. The quantity and the complexity of risk information pose challenges to adequate pre-test and post-test information provision and informed consent. There are currently no guidelines for what should constitute informed consent in PGT or how adequate informed consent can be achieved. In this paper, we propose a tiered-layered-staged model for informed consent. First, the proposed model is tiered as it offers choices between categories of diseases that are associated with distinct ethical, personal or societal issues. Second, the model distinguishes layers of information with a first layer offering minimal, indispensable information that is material to all consumers, and additional layers offering more detailed information made available upon request. Finally, the model stages informed consent as a process by feeding information to consumers in each subsequent stage of the process of undergoing a test, and by accommodating renewed consent for test result updates, resulting from the ongoing development of the science underlying PGT. A tiered-layered-staged model for informed consent with a focus on the consumer perspective can help overcome the ethical problems of information provision and informed consent in direct-to-consumer PGT.European Journal of Human Genetics advance online publication, 21 November 2012; doi:10.1038/ejhg.2012.237

Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: There is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort. METHODS: Women participating in UKCTOCS and diagnosed with EC following enrolment (2001-2005) and prior to 31st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken. RESULTS: 491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months. CONCLUSIONS: In addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.The analysis underpinning this study was supported with a grant from Cancer Research UK (CRUK Grant No: A16008) awarded to RL (http://www.cancerresearchuk. org/funding-for-researchers). The trial (UKCTOCS) for which the patients in this study form a subgroup was funded by the Medical Research Council, Cancer Research UK, the Department of Health and the Eve Appeal

Second-line treatment for primary central nervous system lymphoma

Failure after first-line treatment was reported in 35–60% of immunocompetent patients with primary central nervous system lymphoma (PCNSL). There are currently no reports focusing on salvage therapy. This review analyses prognostic factors and the efficacy of salvage therapy by focusing on data from papers reporting results of first-line treatment in 355 cases. The study group consisted of 173 patients presenting treatment failure. The interval between failure and death (TTD) was compared for age at relapse (≤60 vs >60 years), type of failure (relapse vs progression), time to relapse (≤12 vs >12 months) and salvage treatment (yes vs no). Median TTD was similar in younger and older patients (P = 0.09). Relapsed patients had a longer TTD than patients with progressive disease (P = 0.002). Early relapse led to a shorter TTD than late relapse (P = 0.005). Median TTD was 14 months for patients who underwent salvage therapy and 2 months for untreated cases (P < 0.00001). A multivariate analysis showed an independent prognostic role for salvage therapy and time to relapse. Age and type of failure had no predictive value. Salvage therapy significantly improves outcome and, possibly, quality of life. As many different treatments were used conclusions cannot be made regarding an optimal treatment schedule. © 1999 Cancer Research Campaig

Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a2 = 0.42) and girls (a2 = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity

Molecular mechanisms of EGF signaling-dependent regulation of pipe, a gene crucial for dorsoventral axis formation in Drosophila

During Drosophila oogenesis the expression of the sulfotransferase Pipe in ventral follicle cells is crucial for dorsoventral axis formation. Pipe modifies proteins that are incorporated in the ventral eggshell and activate Toll signaling which in turn initiates embryonic dorsoventral patterning. Ventral pipe expression is the result of an oocyte-derived EGF signal which down-regulates pipe in dorsal follicle cells. The analysis of mutant follicle cell clones reveals that none of the transcription factors known to act downstream of EGF signaling in Drosophila is required or sufficient for pipe regulation. However, the pipe cis-regulatory region harbors a 31-bp element which is essential for pipe repression, and ovarian extracts contain a protein that binds this element. Thus, EGF signaling does not act by down-regulating an activator of pipe as previously suggested but rather by activating a repressor. Surprisingly, this repressor acts independent of the common co-repressors Groucho or CtBP

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Correction to: Nature Genetics https://doi.org/10.1038/ng.3668, published online 26 September 2016. In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs