Concordance of copy number abnormality detection using SNP arrays and Multiplex Ligation-dependent Probe Amplification (MLPA) in acute lymphoblastic leukaemia

In acute lymphoblastic leukaemia, MLPA has been used in research studies to identify clinically relevant copy number abnormality (CNA) profiles. However, in diagnostic settings other techniques are often employed. We assess whether equivalent CNA profiles are called using SNP arrays, ensuring platform independence. We demonstrate concordance between SNP6.0 and MLPA CNA calling on 143 leukaemia samples from two UK trials; comparing 1,287 calls within eight genes and a region. The techniques are 99% concordant using manually augmented calling, and 98% concordant using an automated pipeline. We classify these discordant calls and examine reasons for discordance. In nine cases the circular binary segmentation (CBS) algorithm failed to detect focal abnormalities or those flanking gaps in IKZF1 probe coverage. Eight cases were discordant due to probe design differences, with focal abnormalities detectable using one technique not observable by the other. Risk classification using manually augmented array calling resulted in four out of 143 patients being assigned to a different CNA risk group and eight patients using the automated pipeline. We conclude that MLPA defined CNA profiles can be accurately mirrored by SNP6.0 or similar array platforms. Automated calling using the CBS algorithm proved successful, except for IKZF1 which should be manually inspected

Evolving Health Guidelines: How Do Consumers Fare While Science Marches On?

The press is replete with guidelines regarding preventive behaviors, such as exercise, vitamins, or food choices. Such guidelines may have unintended negative effects on consumers if later reversed. We report a study examining the effect of evolving health guidelines on consumers' initial response and critical "spillover" outcomes-consumers' faith in health guidelines in general and consumers' intention to perform related health behaviors not part of the guideline. We find that a guideline change from taking an action to inaction increases negative spillovers, consistent with omission bias and betrayal aversion. A follow-up experiment with policy implications for mitigating this undesired backlash will also be reported. [to cite]: Christine Moorman, Mary Frances Luce, and James R. Bettman (2008) SESSION OVERVIEW From news reports on the radio, television, internet, and magazines to focused health campaigns targeting susceptible groups, consumers are bombarded with health messages produced by ongoing medical studies, government agencies, for-profit health and insurance firms, and community and public health non-profits. A Google search of "health" produced 939,000,000 hits, "nutrition" produced 148,000,000 hits, and the specific phrases "health news" (6,140,000) and "health communications (651,000) produced a sizable number of hits. These numbers suggest that health messages are a fundamental part of the mosaic of communications consumers encounter every day and constitute a key component of campaigns designed to reduce morbidity and mortality. These numbers and other indicators also point to trends involving increased consumer responsibility for their own care and shifts in medical culture from paternalism towards informed consent. Despite these positive forces, most health communications produce low compliance and rather dismal results. Most health communications are undertaken to alter consumer action. Conventional wisdom is that if health communications are sufficiently informative and persuasive (increasing knowledge, efficacy, or motivation), then appropriate action will follow. This session's papers challenge this wisdom. The first two papers sharpen our understanding of how to use health communication to alter consumer action; the second two papers point to important downstream problems occurring after consumers are motivated to act. Anand Keller and Lehmann report a meta-analysis of 85 health communications studies. They find that message factors, not individual differences or context, dominate explanations of effectiveness. They also show important differences in effects on attitudes toward health behaviors and intentions to change behaviors that may critically influence whether we judge a campaign to be successful or not. Their research underscores the importance of conceptualizing and measuring consumer action (rather than simply consumer attitudes) as a key health communication goal. The second paper, by Anand Keller, extends this theme of the focal nature of consumer action by using mental simulation of healthpromoting actions as a focus of intervention. She challenges the current idea that hope and confidence produce more preventive health behaviors and suggests that increasing consumer anxiety is more effective by producing higher need for action taken to regain control. The third and fourth papers illustrate complementary difficulties in using health communication to alter action. Moorman, Luce, and Bettman argue that consumers may not always benefit from the evolving nature of health guidelines. As medical science sheds more light on the effect of healthy choices or treatment options, communications that initially advocate positive actions (e.g., take a vitamin supplement) but later reverse these suggestions may ultimately degrade consumers' view of health guidelines and decrease their likelihood of performing related health behaviors. Tanner shows that teens may provide inaccurate reports of actions related to risky behaviors when participating in the evaluation of community-based health programs. Inaccuracy is particularly problematic when teens are made aware of desirable health behaviors, when they believe their anonymity may not be protected, or when minimizing, not exaggerating, certain behaviors. Looking across papers, we see several emerging questions regarding the promise and pitfalls of using health communications to alter health behavior: (1) Do health communications work in the short and long-term? Unsurprisingly, numerous studies have assessed the impact of different communication strategies (e.g. level of fear arousal or framing) on subjects' attitudes toward and intentions with respect to various health behaviors. However, the large number of studies and the variability of the findings suggest a quantitative synthesis of this area would be beneficial. The purpose of this paper, therefore, is to assess the current state of knowledge in the field via metaanalysis. In particular, we wanted to identify the context, message and individual factors that increased attitudes and intentions to comply with the recommended health behaviors. For that purpose, we conducted a meta-analysis on data reported in 85 published and unpublished articles in the consumer research, psychology, health, and communications literatures

Perceived Similarity and Relationship Success among Dating Couples: An Idiographic Approach

This study utilized an idiographic approach to investigate the relation between similarity on valued characteristics and relationship success. College students (N = 247) rated their current romantic partner on perceived similarity in personality, attitudes, interests, and religious affiliation; the importance of similarity in these dimensions; and relationship satisfaction. Relationship status was assessed 6 weeks later. Results revealed significant similarity by importance interactions for religion and interests in predicting satisfaction. Participants with high perceived similarity in religion or interests reported greater satisfaction than did their low similarity counterparts, but only to the extent that they rated this type of similarity as being important to them. Similar results were found for attitudes in predicting Time 2 outcomes

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Chamber Formation and Morphogenesis in the Developing Mammalian Heart

AbstractIn this study we challenge the generally accepted view that cardiac chambers form from an array of segmental primordia arranged along the anteroposterior axis of the linear and looping heart tube. We traced the spatial pattern of expression of genes encoding atrial natriuretic factor, sarcoplasmic reticulum calcium ATPase, Chisel, Irx5, Irx4, myosin light chain 2v, and β-myosin heavy chain and related these to morphogenesis. Based on the patterns we propose a two-step model for chamber formation in the embryonic heart. First, a linear heart forms, which is composed of “primary” myocardium that nonetheless shows polarity in phenotype and gene expression along its anteroposterior and dorsoventral axes. Second, specialized ventricular chamber myocardium is specified at the ventral surface of the linear heart tube, while distinct left and right atrial myocardium forms more caudally on laterodorsal surfaces. The process of looping aligns these primordial chambers such that they face the outer curvature. Myocardium of the inner curvature, as well as that of inflow tract, atrioventricular canal, and outflow tract, retains the molecular signature originally found in linear heart tube myocardium. Evidence for distinct transcriptional programs which govern compartmentalization in the forming heart is seen in the patterns of expression of Hand1 for the dorsoventral axis, Irx4 and Tbx5 for the anteroposterior axis, and Irx5 for the distinction between primary and chamber myocardium

Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients