No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer

Background There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study. Methods The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression. Results The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age. Conclusion The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women.

Drivers of technology substitution : successive generations of high tech products

Principal Topic High technology consumer products such as notebooks, digital cameras and DVD players are not introduced into a vacuum. Consumer experience with related earlier generation technologies, such as PCs, film cameras and VCRs, and the installed base of these products strongly impacts the market diffusion of the new generation products. Yet technology substitution has received only sparse attention in the diffusion of innovation literature. Research for consumer durables has been dominated by studies of (first purchase) adoption (c.f. Bass 1969) which do not explicitly consider the presence of an existing product/technology. More recently, considerable attention has also been given to replacement purchases (c.f. Kamakura and Balasubramanian 1987). Only a handful of papers explicitly deal with the diffusion of technology/product substitutes (e.g. Norton and Bass, 1987: Bass and Bass, 2004). They propose diffusion-type aggregate-level sales models that are used to forecast the overall sales for successive generations. Lacking household data, these aggregate models are unable to give insights into the decisions by individual households - whether to adopt generation II, and if so, when and why. This paper makes two contributions. It is the first large-scale empirical study that collects household data for successive generations of technologies in an effort to understand the drivers of adoption. Second, in comparision to traditional analysis that evaluates technology substitution as an ''adoption of innovation'' type process, we propose that from a consumer's perspective, technology substitution combines elements of both adoption (adopting the new generation technology) and replacement (replacing the generation I product with generation II). Based on this proposition, we develop and test a number of hypotheses. Methodology/Key Propositions In some cases, successive generations are clear ''substitutes'' for the earlier generation, in that they have almost identical functionality. For example, successive generations of PCs Pentium I to II to III or flat screen TV substituting for colour TV. More commonly, however, the new technology (generation II) is a ''partial substitute'' for existing technology (generation I). For example, digital cameras substitute for film-based cameras in the sense that they perform the same core function of taking photographs. They have some additional attributes of easier copying and sharing of images. However, the attribute of image quality is inferior. In cases of partial substitution, some consumers will purchase generation II products as substitutes for their generation I product, while other consumers will purchase generation II products as additional products to be used as well as their generation I product. We propose that substitute generation II purchases combine elements of both adoption and replacement, but additional generation II purchases are solely adoption-driven process. Extensive research on innovation adoption has consistently shown consumer innovativeness is the most important consumer characteristic that drives adoption timing (Goldsmith et al. 1995; Gielens and Steenkamp 2007). Hence, we expect consumer innovativeness also to influence both additional and substitute generation II purchases. Hypothesis 1a) More innovative households will make additional generation II purchases earlier. 1 b) More innovative households will make substitute generation II purchases earlier. 1 c) Consumer innovativeness will have a stronger impact on additional generation II purchases than on substitute generation II purchases. As outlined above, substitute generation II purchases act, in part like a replacement purchase for the generation I product. Prior research (Bayus 1991; Grewal et al 2004) identified product age as the most dominant factor influencing replacements. Hence, we hypothesise that: Hypothesis 2: Households with older generation I products will make substitute generation II purchases earlier. Our survey of 8,077 households investigates their adoption of two new generation products: notebooks as a technology change to PCs, and DVD players as a technology shift from VCRs. We employ Cox hazard modelling to study factors influencing the timing of a household's adoption of generation II products. We determine whether this is an additional or substitute purchase by asking whether the generation I product is still used. A separate hazard model is conducted for additional and substitute purchases. Consumer Innovativeness is measured as domain innovativeness adapted from the scales of Goldsmith and Hofacker (1991) and Flynn et al. (1996). The age of the generation I product is calculated based on the most recent household purchase of that product. Control variables include age, size and income of household, and age and education of primary decision-maker. Results and Implications Our preliminary results confirm both our hypotheses. Consumer innovativeness has a strong influence on both additional purchases (exp = 1.11) and substitute purchases (exp = 1.09). Exp is interpreted as the increased probability of purchase for an increase of 1.0 on a 7-point innovativeness scale. Also consistent with our hypotheses, the age of the generation I product has a dramatic influence for substitute purchases of VCR/DVD (exp = 2.92) and a strong influence for PCs/notebooks (exp = 1.30). Exp is interpreted as the increased probability of purchase for an increase of 10 years in the age of the generation I product. Yet, also as hypothesised, there was no influence on additional purchases. The results lead to two key implications. First, there is a clear distinction between additional and substitute purchases of generation II products, each with different drivers. Treating these as a single process will mask the true drivers of adoption. For substitute purchases, product age is a key driver. Hence, implications for marketers of high technology products can utilise data on generation I product age (e.g. from warranty or loyalty programs) to target customers who are more likely to make a purchase.

Linkage and heritability analysis of migraine symptom groupings: A comparison of three different clustering methods on twin data

Migraine is a painful disorder for which the etiology remains obscure. Diagnosis is largely based on International Headache Society criteria. However, no feature occurs in all patients who meet these criteria, and no single symptom is required for diagnosis. Consequently, this definition may not accurately reflect the phenotypic heterogeneity or genetic basis of the disorder. Such phenotypic uncertainty is typical for complex genetic disorders and has encouraged interest in multivariate statistical methods for classifying disease phenotypes. We applied three popular statistical phenotyping methods—latent class analysis, grade of membership and grade of membership “fuzzy” clustering (Fanny)—to migraine symptom data, and compared heritability and genome-wide linkage results obtained using each approach. Our results demonstrate that different methodologies produce different clustering structures and non-negligible differences in subsequent analyses. We therefore urge caution in the use of any single approach and suggest that multiple phenotyping methods be used.

Methods and preliminary results for a data linkage project to determine long-term survival after intensive care unit admission

Aims: To describe a local data linkage project to match hospital data with the Australian Institute of Health and Welfare (AIHW) National Death Index (NDI) to assess longterm outcomes of intensive care unit patients. Methods: Data were obtained from hospital intensive care and cardiac surgery databases on all patients aged 18 years and over admitted to either of two intensive care units at a tertiary-referral hospital between 1 January 1994 and 31 December 2005. Date of death was obtained from the AIHW NDI by probabilistic software matching, in addition to manual checking through hospital databases and other sources. Survival was calculated from time of ICU admission, with a censoring date of 14 February 2007. Data for patients with multiple hospital admissions requiring intensive care were analysed only from the first admission. Summary and descriptive statistics were used for preliminary data analysis. Kaplan-Meier survival analysis was used to analyse factors determining long-term survival. Results: During the study period, 21 415 unique patients had 22 552 hospital admissions that included an ICU admission; 19 058 surgical procedures were performed with a total of 20 092 ICU admissions. There were 4936 deaths. Median follow-up was 6.2 years, totalling 134 203 patient years. The casemix was predominantly cardiac surgery (80%), followed by cardiac medical (6%), and other medical (4%). The unadjusted survival at 1, 5 and 10 years was 97%, 84% and 70%, respectively. The 1-year survival ranged from 97% for cardiac surgery to 36% for cardiac arrest. An APACHE II score was available for 16 877 patients. In those discharged alive from hospital, the 1, 5 and 10-year survival varied with discharge location. Conclusions: ICU-based linkage projects are feasible to determine long-term outcomes of ICU patients

Access to medicine and the dangers of patent linkage : lessons from Bayer Corp v. Union of India

In February 2010, the Delhi High Court delivered its decision in Bayer Corp v Union of India in which Bayer had appealed against an August 2009 decision of the same court. Both decisions prevented Bayer from introducing the concept of patent linkage into India’s drug regulatory regime. Bayer appealed to the Indian Supreme Court, the highest court in India, which agreed on 2 March 2010 to hear the appeal. Given that India is regarded as a global pharmaceutical manufacturer of generic medications, how its judiciary and government perceive their international obligations has a significant impact on the global access to medicines regime. In rejecting the application of patent linkage, the case provides an opportunity for India to further acknowledge its international human rights obligations.

The factor V HR2 haplotype: Prevalence and association of the A4070G and A6755G polymorphisms

Recently, a polymorphism was identified in exon 25 of the factor V gene that is possibly a functional candidate for the HR2 haplotype. This haplotype is characterized by a single base substitution named R2 (A4070G) in the B domain of the protein. A mutation (A6755G; 2194Asp→Gly) located near the C terminus has been hypothesized to influence protein folding and glycosylation, and might be responsible for the shift in factor V isoform (FV1 / FV2) ratio. This study investigated the prevalence of these two factor V HR2 haplotype polymorphisms in a cohort of normal blood donors, patients with osteoarthritis and women with complications during pregnancy, and in families of factor V Leiden individuals. A high allele frequency for the two polymorphisms was found in the blood donor group (6.2% R2, 5.6% A6755G). No significant difference in allele frequency was observed in the clinical groups (obstetric complications and osteoarthritis, 4.1-4.9% for the two polymorphisms) when compared with that of healthy blood donors. We confirm that the factor V A6755G polymorphism shows strong linkage to the R2 allele, although it is not exclusively inherited with the exon 13 A4070G variant and can occur independently. © 2001 Lippincott Williams & Wilkins.

Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Abstract Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identified in a proportion of melanoma kindreds. In the case of CDK4, only one specific mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identification of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1beta) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M531 substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous findings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the 'CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.

Creating better learning environments by cross-disciplinary collaboration : a civil engineering and surveying linkage

Many of the teaching elements in Civil and Environmental Engineering and Spatial Science/Surveying are strongly related to multidisciplinary real-world situations. Professionals in each discipline commonly work collaboratively, knowing each other’s professional and technical limitations and requirements. Replication of such real-world situations allows students to gain an insight and acquire knowledge of professional practice for both civil engineering and spatial science disciplines. However, replication of an authentic design project is not always possible in a single unit basis where empirical project situations are often created with controlled sets of constraints, inputs and outputs. A cross-disciplinary design-based project that is designed to promote active student learning, engagement and professional integration would be the preferred option. The central aim of this collaborative project was to create positive and inclusive environments to promote engaging learning opportunities that cater for a range of learning styles with a two-way linkage involving third-year civil engineering and spatial science (surveying) students. This paper describes the cross-disciplinary project developed and delivered in 2010 and 2011. A survey was conducted at completion of the project to assess the degree of improvement in student engagement and their learning experiences. Improvements were assessed in a range of dimensions including student motivation, learning by cross-disciplinary collaboration and learning by authentic design project experiences. In this specific cross-disciplinary linkage project, the study findings showed that teaching approaches utilised have been effective in promoting active student learning and increasing engagement.

Assessing the effectiveness of the child safety net : linkage of hospital and child protection services data on ‘maltreated’ and ‘unintentionally injured' children

-International recognition of need for public health response to child maltreatment -Need for early intervention at health system level -Important role of health professionals in identifying, reporting, documenting suspician of maltreatment -Up to 10% of all children presenting at ED’s are victims and without identification, 35% reinjured and 5% die -In Qld, mandatory reporting requirement for doctors and nurses for suspected abuse or neglect