Showing papers by "University of Iowa published in 2008"

Meta-Analysis: A Constantly Evolving Research Integration Tool

Abstract: During the past 30 years, meta-analysis has been an indispensable tool for revealing the hidden meaning of our research literatures. The four articles in this special section on meta-analysis illus...

The CMS experiment at the CERN LHC

Abstract: The Compact Muon Solenoid (CMS) detector is described. The detector operates at the Large Hadron Collider (LHC) at CERN. It was conceived to study proton-proton (and lead-lead) collisions at a centre-of-mass energy of 14 TeV (5.5 TeV nucleon-nucleon) and at luminosities up to 10(34)cm(-2)s(-1) (10(27)cm(-2)s(-1)). At the core of the CMS detector sits a high-magnetic-field and large-bore superconducting solenoid surrounding an all-silicon pixel and strip tracker, a lead-tungstate scintillating-crystals electromagnetic calorimeter, and a brass-scintillator sampling hadron calorimeter. The iron yoke of the flux-return is instrumented with four stations of muon detectors covering most of the 4 pi solid angle. Forward sampling calorimeters extend the pseudo-rapidity coverage to high values (vertical bar eta vertical bar <= 5) assuring very good hermeticity. The overall dimensions of the CMS detector are a length of 21.6 m, a diameter of 14.6 m and a total weight of 12500 t.

Global and regional climate changes due to black carbon

Abstract: Black carbon in soot is an efficient absorbing agent of solar irradiation that is preferentially emitted in the tropics and can form atmospheric brown clouds in mixture with other aerosols. These factors combine to make black carbon emissions the second most important contribution to anthropogenic climate warming, after carbon dioxide emissions.

A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.

Abstract: Understanding the cell–cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100β promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of >20,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin αvβ5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a “glial” cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease.

Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis

Abstract: S um m a r y Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investiga t ed the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carry- ing RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event pro- file after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study pro- vides the basis for further gene therapy studies in patients with LCA.

Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.

Abstract: Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.

Discrete fixed-resolution representations in visual working memory

Abstract: Limits on the storage capacity of working memory significantly affect cognitive abilities in a wide range of domains, but the nature of these capacity limits has been elusive. Some researchers have proposed that working memory stores a limited set of discrete, fixed-resolution representations, whereas others have proposed that working memory consists of a pool of resources that can be allocated flexibly to provide either a small number of high-resolution representations or a large number of low-resolution representations. Here we resolve this controversy by providing independent measures of capacity and resolution. We show that, when presented with more than a few simple objects, human observers store a high-resolution representation of a subset of the objects and retain no information about the others. Memory resolution varied over a narrow range that cannot be explained in terms of a general resource pool but can be well explained by a small set of discrete, fixed-resolution representations.

Continuous glucose monitoring and intensive treatment of type 1 diabetes.

Abstract: BACKGROUND The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Motivation and self-regulated learning : theory, research, and applications

Abstract: This volume focuses on the role of motivational processes - such as goals, attributions, self-efficacy, outcome expectations, self-concept, self-esteem, social comparisons, emotions, values, and self-evaluations- in self-regulated learning. It provides theoretical and empirical evidence demonstrating the role of motivation in self-regulated learning, and discusses detailed applications of the principles of motivation and self-regulation in educational contexts. Each chapter includes a description of the motivational variables, the theoretical rationale for their importance, research evidence to support their role in self-regulation, suggestions for ways to incorporate motivational variables into learning contexts to foster self-regulatory skill development, and achievement outcomes.

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.

Abstract: Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.

Identification of loci associated with schizophrenia by genome-wide association and follow-up

Abstract: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).

New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure

Abstract: Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.

Revisiting the Conceptualisation of Pedagogical Content Knowledge (PCK): PCK as a Conceptual Tool to Understand Teachers as Professionals

Abstract: The purpose of this study was to rethink the conceptualization of pedagogical content knowledge based on our descriptive research findings and to show how this new conceptualization helps us to understand teachers as professionals. This study was a multiple case study grounded in a social constructivist framework. Data were collected from multiple sources and analysed using three approaches: (a) constant comparative method, (b) enumerative approach, and (c) in-depth analysis of explicit PCK. The results indicated that (a) PCK was developed through reflection-in-action and reflection-on-action within given instructional contexts, (b) teacher efficacy emerged as an affective affiliate of PCK, (c) students had an important impact on PCK development, (d) students’ misconceptions played a significant role in shaping PCK, and (e) PCK was idiosyncratic in some aspects of its enactment. Discussion centres on how these five aspects are related to teacher professionalism.

The Nalp3 inflammasome is essential for the development of silicosis

Abstract: Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1β and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

Detection of Huntington’s disease decades before diagnosis: The Predict HD study

Abstract: Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs.

Abstract: Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.

The sparsity and bias of the Lasso selection in high-dimensional linear regression

Abstract: Meinshausen and Buhlmann [Ann. Statist. 34 (2006) 1436--1462] showed that, for neighborhood selection in Gaussian graphical models, under a neighborhood stability condition, the LASSO is consistent, even when the number of variables is of greater order than the sample size. Zhao and Yu [(2006) J. Machine Learning Research 7 2541--2567] formalized the neighborhood stability condition in the context of linear regression as a strong irrepresentable condition. That paper showed that under this condition, the LASSO selects exactly the set of nonzero regression coefficients, provided that these coefficients are bounded away from zero at a certain rate. In this paper, the regression coefficients outside an ideal model are assumed to be small, but not necessarily zero. Under a sparse Riesz condition on the correlation of design variables, we prove that the LASSO selects a model of the correct order of dimensionality, controls the bias of the selected model at a level determined by the contributions of small regression coefficients and threshold bias, and selects all coefficients of greater order than the bias of the selected model. Moreover, as a consequence of this rate consistency of the LASSO in model selection, it is proved that the sum of error squares for the mean response and the $\ell_{\alpha}$-loss for the regression coefficients converge at the best possible rates under the given conditions. An interesting aspect of our results is that the logarithm of the number of variables can be of the same order as the sample size for certain random dependent designs.

Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis: A Randomized Controlled Trial

Abstract: Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119

The sparsity and bias of the Lasso selection in high-dimensional linear regression

Abstract: Meinshausen and Buhlmann [Ann. Statist. 34 (2006) 1436–1462] showed that, for neighborhood selection in Gaussian graphical models, under a neighborhood stability condition, the LASSO is consistent, even when the number of variables is of greater order than the sample size. Zhao and Yu [(2006) J. Machine Learning Research 7 2541–2567] formalized the neighborhood stability condition in the context of linear regression as a strong irrepresentable condition. That paper showed that under this condition, the LASSO selects exactly the set of nonzero regression coefficients, provided that these coefficients are bounded away from zero at a certain rate. In this paper, the regression coefficients outside an ideal model are assumed to be small, but not necessarily zero. Under a sparse Riesz condition on the correlation of design variables, we prove that the LASSO selects a model of the correct order of dimensionality, controls the bias of the selected model at a level determined by the contributions of small regression coefficients and threshold bias, and selects all coefficients of greater order than the bias of the selected model. Moreover, as a consequence of this rate consistency of the LASSO in model selection, it is proved that the sum of error squares for the mean response and the lα-loss for the regression coefficients converge at the best possible rates under the given conditions. An interesting aspect of our results is that the logarithm of the number of variables can be of the same order as the sample size for certain random dependent designs.

The Effect of SOX Internal Control Deficiencies on Firm Risk and Cost of Equity

Abstract: The Sarbanes-Oxley Act (SOX) mandates management evaluation and independent audits of internal control effectiveness. The mandate is costly to firms but may yield benefits through lower information risk that translates into lower cost of equity. We use unaudited pre-SOX 404 disclosures and SOX 404 audit opinions to assess how changes in internal control quality affect firm risk and cost of equity. After controlling for other risk factors, we find that firms with internal control deficiencies have significantly higher idiosyncratic risk, systematic risk, and cost of equity. Our change analyses document that auditor-confirmed changes in internal control effectiveness (including remediation of previously disclosed internal control deficiencies) are followed by significant changes in the cost of equity that range from 50 to 150 basis points. Overall, our cross-sectional and inter-temporal change test results are consistent with internal control reports affecting investors' risk assessments and firms' cost of equity.

The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease.

Abstract: The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered in the cytoplasm in part through binding to huntingtin. Polyglutamine expansions in huntingtin, which causes Huntington's disease (HD), abrogates REST-huntingtin binding. Consequently, REST translocates to the nucleus, occupies RE1 repressor sequences and decreases neuronal gene expression. In this work, we found that levels of several microRNAs (miRNAs) with upstream RE1 sites are decreased in HD patient cortices relative to healthy controls. Interestingly, one of these, the bifunctional brain enriched miR-9/miR-9*, targets two components of the REST complex: miR-9 targets REST and miR-9* targets CoREST. These data provide evidence for a double negative feedback loop between the REST silencing complex and the miRNAs it regulates.

The Effect of SOX Internal Control Deficiencies and Their Remediation on Accrual Quality

Abstract: This paper investigates the effect of internal control deficiencies and their remediation on accrual quality. We first document that firms reporting internal control deficiencies have lower quality accruals as measured by accrual noise and absolute abnormal accruals relative to firms not reporting internal control problems. Second, we find that firms that report internal control deficiencies have significantly larger positive and larger negative abnormal accruals relative to control firms. This finding suggests internal control weaknesses are more likely to lead to unintentional errors that add noise to accruals than intentional misstatements that bias earnings upward. Third, we doc- ument that firms whose auditors confirm remediation of previously reported internal control deficiencies exhibit an increase in accrual quality relative to firms that do not remediate their control problems. Finally, we find firms that receive different internal control audit opinions in successive years exhibit changes in accrual quality consistent with changes in internal control quality. Collectively, our cross-sectional and intertem- poral change tests provide strong evidence that the quality of internal control affects the quality of accruals.

Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi

Abstract: Huntington's disease (HD) is a fatal, dominant neurodegenerative disease caused by a polyglutamine repeat expansion in exon 1 of the HD gene, which encodes the huntingtin protein. We and others have shown that RNAi is a candidate therapy for HD because expression of inhibitory RNAs targeting mutant human HD transgenes improved neuropathology and behavioral deficits in HD mouse models. Here, we developed shRNAs targeting conserved sequences in human HD and mouse HD homolog (HDh) mRNAs to initiate preclinical testing in a knockin mouse model of HD. We screened 35 shRNAs in vitro and subsequently narrowed our focus to three candidates for in vivo testing. Unexpectedly, two active shRNAs induced significant neurotoxicity in mouse striatum, although HDh mRNA expression was reduced to similar levels by all three. Additionally, a control shRNA containing mismatches also induced toxicity, although it did not reduce HDh mRNA expression. Interestingly, the toxic shRNAs generated higher antisense RNA levels, compared with the nontoxic shRNA. These results demonstrate that the robust levels of antisense RNAs emerging from shRNA expression systems can be problematic in the mouse brain. Importantly, when sequences that were toxic in the context of shRNAs were placed into artificial microRNA (miRNA) expression systems, molecular and neuropathological readouts of neurotoxicity were significantly attenuated without compromising mouse HDh silencing efficacy. Thus, miRNA-based approaches may provide more appropriate biological tools for expressing inhibitory RNAs in the brain, the implications of which are crucial to the development of RNAi for both basic biological and therapeutic applications.

Adaptive Lasso for sparse high-dimensional regression models

Abstract: We study the asymptotic properties of the adaptive Lasso estimators in sparse, high-dimensional, linear regression models when the number of covariates may increase with the sample size. We consider variable selection using the adap- tive Lasso, where the L1 norms in the penalty are re-weighted by data-dependent weights. We show that, if a reasonable initial estimator is available, under ap- propriate conditions, the adaptive Lasso correctly selects covariates with nonzero coefficients with probability converging to one, and that theestimators of nonzero coefficients have the same asymptotic distribution they would have if the zero co- efficients were known in advance. Thus, the adaptive Lasso hasan oracle property in the sense of Fan and Li (2001) and Fan and Peng (2004). In addition, under a partial orthogonality condition in which the covariates with zero coefficients are weakly correlated with the covariates with nonzero coefficients, marginal regression can be used to obtain the initial estimator. With this initial estimator, the adaptive Lasso has the oracle property even when the number of covariates is much larger than the sample size.

Using internet searches for influenza surveillance.

Abstract: The Internet is an important source of health information. Thus, the frequency of Internet searches may provide information regarding infectious disease activity. As an example, we examined the relationship between searches for influenza and actual influenza occurrence. Using search queries from the Yahoo! search engine ( http://search.yahoo.com ) from March 2004 through May 2008, we counted daily unique queries originating in the United States that contained influenza-related search terms. Counts were divided by the total number of searches, and the resulting daily fraction of searches was averaged over the week. We estimated linear models, using searches with 1-10-week lead times as explanatory variables to predict the percentage of cultures positive for influenza and deaths attributable to pneumonia and influenza in the United States. With use of the frequency of searches, our models predicted an increase in cultures positive for influenza 1-3 weeks in advance of when they occurred (P < .001), and similar models predicted an increase in mortality attributable to pneumonia and influenza up to 5 weeks in advance (P < .001). Search-term surveillance may provide an additional tool for disease surveillance.