PopMod: a longitudinal population model with two interacting disease states

This article provides a description of the population model PopMod, which is designed to simulate the health and mortality experience of an arbitrary population subjected to two interacting disease conditions as well as all other "background" causes of death and disability. Among population models with a longitudinal dimension, PopMod is unique in modelling two interacting disease conditions; among the life-table family of population models, PopMod is unique in not assuming statistical independence of the diseases of interest, as well as in modelling age and time independently. Like other multi-state models, however, PopMod takes account of "competing risk" among diseases and causes of death. PopMod represents a new level of complexity among both generic population models and the family of multi-state life tables. While one of its intended uses is to describe the time evolution of population health for standard demographic purposes (e.g. estimates of healthy life expectancy), another prominent aim is to provide a standard measure of effectiveness for intervention and cost-effectiveness analysis. PopMod, and a set of related standard approaches to disease modelling and cost-effectiveness analysis, will facilitate disease modelling and cost-effectiveness analysis in diverse settings and help make results more comparable

Potential of polygenic risk scores for improving population estimates of women’s breast cancer genetic risks

Funder: Genome Canada; doi: https://doi.org/10.13039/http://dx.doi.org/10.13039/100008762Abstract: Purpose: Breast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2, and more recently PALB2, CHEK2, and ATM. In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown. Methods: The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known. Results: Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer. Conclusion: PRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening

Mapping translocation breakpoints using a wheat microarray

We report mapping of translocation breakpoints using a microarray. We used complex RNA to compare normal hexaploid wheat (17 000 Mb genome) to a ditelosomic stock missing the short arm of chromosome 1B (1BS) and wheat-rye translocations that replace portions of 1BS with rye 1RS. Transcripts detected by a probe set can come from all three Triticeae genomes in ABD hexaploid wheat, and sequences of homoeologous genes on 1AS, 1BS and 1DS often differ from each other. Absence or replacement of 1BS therefore must sometimes result in patterns within a probe set that deviate from hexaploid wheat. We termed these ‘high variance probe sets’ (HVPs) and examined the extent to which HVPs associated with 1BS aneuploidy are related to rice genes on syntenic rice chromosome 5 short arm (5S). We observed an enrichment of such probe sets to 15–20% of all HVPs, while 1BS represents ∼2% of the total genome. In total 257 HVPs constitute wheat 1BS markers. Two wheat-rye translocations subdivided 1BS HVPs into three groups, allocating translocation breakpoints to narrow intervals defined by rice 5S coordinates. This approach could be extended to the entire wheat genome or any organism with suitable aneuploid or translocation stocks

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

SECURITY cTPM A Cloud TPM for Cross-Device Trusted Applications

C urrent Trusted Platform Modules (TPMs) are ill-suited for use in mobile services because they hinder sharing data across multiple devices seamlessly, they lack access to a trusted real-time clock, and their non-volatile storage performs poorly. We present cloud TPM (cTPM), an extension of the TPM's design, to address these problems. cTPM includes two features: a cloud seed shared between the TPM and the cloud, and remote storage in addition to the on-chip storage. cTPM allows the cloud to create and share TPM-protected keys across multiple devices, to manage a portion of a mobile device's TPM storage, and to provide each TPM with a trusted real-time clock and with high-performance non-volatile storage. Introduction People are increasingly relying on more than one mobile device. Recent news reports estimate that the average US consumer owns 1.57 mobile devices; Singapore has 7.8 million mobile devices, which translates to 150% mobile penetration; and the average Australian will own five mobile devices by 2040. Given this trend, mobile platforms are recognizing the need for "cross-device" functionality that automatically synchronizes photos, videos, apps, data, and even games across all devices owned by a single user. Mobile platforms, such as laptops, smartphones, and tablets, are increasingly incorporating trusted computing hardware. For example, Google's Chromebooks use TPM to prevent firmware rollbacks and to store and attest a user's data encryption keys. Windows 8 (on tablets and phones) offers BitLocker full-disk encryption and virtual smart cards using TPMs. Recent research leverages TPMs to build new trusted mobile services Unfortunately, these two trends may be at odds: Trusted hardware, such as the TPM, does not provide good support for cross-device functionality. Specifically, we have identified three limitations in the TPM design that hamper building cross-device trusted applications. Limitation 1: Cross-Device Data Sharing. Current TPM abstractions offer guarantees about one single computer, and TPM's hardware protection mechanisms do not extend across devices. For example, TPM's owner domain provides an isolation mechanism for only a single TPM. A new owner of the TPM cannot access the previous owner's TPM-protected secrets. When the same user owns two different TPMs (on two different devices), the owner domains of each TPM remain isolated and cannot jointly offer hardware-based protection of the user's keys and data. Thus, mobile services cannot rely on TPMs alone to enable secure data sharing across devices. While, in theory, migrating a TPM-protected key from one TPM to another is possible, in practice, it requires using secure execution mode (SEM), such as Intel's TXT and AMD's SEM, and trusting a third-party PKI. Such requirements are very challenging. Our NSDI paper [2] describes in more depth the nature of these challenges. Limitation 2: Trusted Clock. Today's TPMs do not offer a trusted real-time clock. Instead, the TPM combines a trusted timer with a secure, volatile counter, which is periodically persisted to the TPM's NV storage. However, this mechanism can keep track of time only when the TPM is running (and not when the platform is powered off). Moreover, after an unclean reboot, the timer is rolled back to the last persisted counter value violating monotonicity. The TPM's timer mechanism solely guarantees that as long as the platform does not reboot, the timer will move forward. As such, it can provide an approximate time-since-boot. This mechanism is inadequate for offering real-time guarantees that would be useful for offline content access. For example, movie studios already charge a premium to make a movie available on home theaters on the day of release. Although TPMs can provide offline access securely, they cannot offer making the new movie available for watching next Friday at midnight. Limitation 3: Non-Volatile (NV) Storage. The TPM's NV storage is inadequate for applications that require frequent writes or require large amounts of trusted storage. For example, previous work Overcoming these limitations requires altering the TPM design, which raises the following question: Can a small-scale TPM design change overcome these limitations? Although a cleanslate TPM redesign could provide a variety of additional security properties, there are two pragmatic reasons why a smaller change is preferable. First, TPMs have undergone a decade of API and implementation revisions to reduce the likelihood of vulnerabilities. A clean-slate redesign would demand considerable time and effort to provide a mature code base. Second, TPM manufacturers would more willingly adopt smaller and simpler changes. To address these limitations, we propose a single, simple modification to the TPM design, called cTPM: equipping the TPM with one primary seed that is shared with the cloud. Sharing the seed with the cloud allows both cTPM and the cloud to generate the same cloud root key. Combining the cloud root key with remote storage lets cTPM: (1) share data via the cloud, (2) have access to a trusted real-time clock, and (3) have access to remote NV storage that supports a large quantity of storage and high frequency writes. cTPM's design facilitates data sharing. The pre-shared primary seed lets the cloud effectively act as a PKI. The cloud and the device's TPM can use this shared secret to encrypt and authenticate their messages to each other. The identity problem has now been "pushed" to ensuring that the cloud primary seed is shared securely between cTPM and the cloud. This initial sharing step should be done at cTPM manufacturing time when the cTPM's three other primary seeds are provisioned. The pre-shared primary seed also equips cTPM with a trusted clock using a protocol similar to the Time Protocol described in RFC 868. Once the clock value is obtained from the cloud, cTPM uses its local timer to advance the clock. It has a global variable that dictates how often it should resynchronize the clock; the TPM owner sets this variable whose default value is one day. Finally, cTPM uses the cloud for additional NV storage to overcome TPM NV storage limitations. There are no limits on how much additional NV storage the cloud can provide to a single cTPM. A portion of the physical cTPM chip's RAM is thus allocated as a local cach

A streamlined life-cycle assessment and decision tool for used tyres recycling

In order to achieve progress towards sustainable resource management, it is essential to evaluate options for the reuse and recycling of secondary raw materials, in order to provide a robust evidence base for decision makers. This paper presents the research undertaken in the development of a web-based decision-support tool (the used tyres resource efficiency tool) to compare three processing routes for used tyres compared to their existing primary alternatives. Primary data on the energy and material flows for the three routes, and their alternatives were collected and analysed. The methodology used was a streamlined life-cycle assessment (sLCA) approach. Processes included were: car tyre baling against aggregate gabions; car tyre retreading against new car tyres; and car tyre shred used in landfill engineering against primary aggregates. The outputs of the assessment, and web-based tool, were estimates of raw materials used, carbon dioxide emissions and costs. The paper discusses the benefits of carrying out a streamlined LCA and using the outputs of this analysis to develop a decision-support tool. The strengths and weakness of this approach are discussed and future research priorities identified which could facilitate the use of life cycle approaches by designers and practitioners

Dynamically fault-tolerant content addressable networks

\Lambda Abstract We describe a content addressable network which is robust in the face of massive adversarial attacks and in a highly dynamic environment. Our network is robust in the sense that at any time, an arbitrarily large fraction of the peers can reach an arbitrarily large fraction of the data items. The network can be created and maintained in a completely distributed fashion. 1 Introduction Distributed denial-of-service attacks on the Internet are highly prevalent, targeting a wide-range of victims [3]. Peer-to-peer systems are particularly vulnerable to such attacks, since peers lack the technical expertise and resources needed for maintaining a high level of protection. In addition to being vulnerable to such attacks, we can expect peer-to-peer systems to be confronted with a highly dynamic peer turnover rate [8]. For example, in both Napster and Gnutella, half of the peers participating in the system will be replaced by new peers within one hour. Thus, maintaining fault-tolerance in the face of massive targeted attacks and in a highly dynamic environment is critical to the success of a peer-to-peer system. The contributions of this paper are two-fold. First, we define the notion of dynamically strong fault-tolerance. Our definition captures the properties that a peer-to-peer system must have to be robust to orchestrated attacks and in a highly dynamic environment. Second, we present a content addressable network [9] which is dynamically strong faulttolerant