Recent years have seen a wave of laws making it more difficult to vote in the United States. Their ostensible purpose is to prevent voting by persons not legally qualified, and thus to improve public confidence in electoral integrity. Are such laws in fact needed to address serious fraud problems? On the other hand, how many and what kinds of legitimate voters will be, or have been, disenfranchised by them? Is voter confidence positively, or negatively, affected by voter ID laws? This article surveys what is known about these issues and offers suggestions for how statisticians can contribute.
From the Preface: The Centers for Medicare and Medicaid Services (CMS), through a subcontract with Yale New Haven Health Services Corporation, Center for Outcomes Research and Evaluation (YNHHSC/CORE), is supporting a committee appointed by the Committee of Presidents of Statistical Societies (COPSS) to address statistical issues identified by the CMS and stakeholders about CMS’s approach to modeling hospital quality based on outcomes. In the spring of 2011, with the direct support of YNHHSC/ CORE, COPSS formed a committee comprised of one member from each of its constituent societies, a chair, and a staff member from the American Statistical Association, and held a preliminary meeting in April. In June, YNHHSC/CORE executed a subcontract with COPSS under its CMS contract to support the development of a White Paper on statistical modeling. Specifically, YNHHSC/CORE contracted with COPSS to “provide guidance on statistical approaches . . .when estimating performance metrics,” and “consider and discuss concerns commonly raised by stakeholders (hospitals, consumer, and insurers) about the use of “hierarchical generalized linear models in profiling hospital quality. The committee convened in June and August of 2011, and exchanged a wide variety of materials. To ensure the committee’s independence, YNHHSC/CORE did not comment on the white paper findings, and CMS pre-cleared COPSS’ publication of an academic manuscript based on the White Paper.
INR targets and site-level anticoagulation control: results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA)
BACKGROUND: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2-3. A patient's mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR).
OBJECTIVES: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care.
PATIENTS/METHODS: We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site-level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk-adjusted TTR.
RESULTS: Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites' proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (P < 0.001).
CONCLUSIONS: Proportion of patients with mean INR near 2.5 is a site-level 'signature' of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.
BACKGROUND: Warfarin is effective in preventing thromboembolic events, but concerns exist regarding its use in patients with substance abuse.
OBJECTIVE: Identify which patients with substance abuse who receive warfarin are at risk for poor outcomes.
DESIGN: Retrospective cohort study. Diagnostic codes, lab values, and other factors were examined to identify risk of adverse outcomes.
PATIENTS: Veterans AffaiRs Study to Improve Anticoagulation (VARIA) database of 103,897 patients receiving warfarin across 100 sites.
MAIN MEASURES: Outcomes included percent time in therapeutic range (TTR), a measure of anticoagulation control, and major hemorrhagic events by ICD-9 codes.
RESULTS: Nonusers had a higher mean TTR (62 %) than those abusing alcohol (53 %), drugs (50 %), or both (44 %, p < 0.001). Among alcohol abusers, an increasing ratio of the serum hepatic transaminases aspartate aminotransferase/alanine aminotransferase (AST:ALT) correlated with inferior anticoagulation control; normal AST:ALT ≤ 1.5 predicted relatively modest decline in TTR (54 %, p < 0.001), while elevated ratios (AST:ALT 1.50-2.0 and > 2.0) predicted progressively poorer anticoagulation control (49 % and 44 %, p < 0.001 compared to nonusers). Age-adjusted hazard ratio for major hemorrhage was 1.93 in drug and 1.37 in alcohol abuse (p < 0.001 compared to nonusers), and remained significant after also controlling for anticoagulation control and other bleeding risk factors (1.69 p < 0.001 and 1.22 p = 0.003). Among alcohol abusers, elevated AST:ALT >2.0 corresponded to more than three times the hemorrhages (HR 3.02, p < 0.001 compared to nonusers), while a normal ratio AST:ALT ≤ 1.5 predicted a rate similar to nonusers (HR 1.19, p < 0.05).
CONCLUSIONS: Anticoagulation control is particularly poor in patients with substance abuse. Major hemorrhages are more common in both alcohol and drug users. Among alcohol abusers, the ratio of AST/ALT holds promise for identifying those at highest risk for adverse events.
Using the bootstrap to establish statistical significance for relative validity comparisons among patient-reported outcome measures
BACKGROUND: Relative validity (RV), a ratio of ANOVA F-statistics, is often used to compare the validity of patient-reported outcome (PRO) measures. We used the bootstrap to establish the statistical significance of the RV and to identify key factors affecting its significance.
METHODS: Based on responses from 453 chronic kidney disease (CKD) patients to 16 CKD-specific and generic PRO measures, RVs were computed to determine how well each measure discriminated across clinically-defined groups of patients compared to the most discriminating (reference) measure. Statistical significance of RV was quantified by the 95% bootstrap confidence interval. Simulations examined the effects of sample size, denominator F-statistic, correlation between comparator and reference measures, and number of bootstrap replicates.
RESULTS: The statistical significance of the RV increased as the magnitude of denominator F-statistic increased or as the correlation between comparator and reference measures increased. A denominator F-statistic of 57 conveyed sufficient power (80%) to detect an RV of 0.6 for two measures correlated at r = 0.7. Larger denominator F-statistics or higher correlations provided greater power. Larger sample size with a fixed denominator F-statistic or more bootstrap replicates (beyond 500) had minimal impact.
CONCLUSIONS: The bootstrap is valuable for establishing the statistical significance of RV estimates. A reasonably large denominator F-statistic (F > 57) is required for adequate power when using the RV to compare the validity of measures with small or moderate correlations (r < 0.7). Substantially greater power can be achieved when comparing measures of a very high correlation (r > 0.9).
The factors that limit primary care providers (PCPs) from intervening for adults with evolving acute severe illness are less understood than the increasing frequency of management by acute care providers.
Rates of pre-hospital patient management by a PCP and of communication with the acute care teams were measured in a multi-center cross sectional descriptive study conducted in all four of the adult medical intensive care units (ICU) of the 3 hospitals in central Massachusetts that provide tertiary care. Rates were measured for 390 critical care encounters using a validated instrument to abstract the medical record and conduct telephone interviews.
PCPs implemented pre-hospital management for 8 episodes of acute illness among 300 encounters. Infrequent pre-hospital management by PCPs was attributed to their lack of awareness of the patient's evolving acute illness. Only 21% of PCPs were aware of the acute illness before their patient was admitted to an ICU and 33% were not aware that their patient was in an ICU. Rates of PCP involvement were not appreciably different among provider groups, by patient age, sex, insurance status, hospital, ICU, or ICU staffing model.
We identified lack of PCP awareness of the acute illness and high rates of PCP referral to acute care providers as the most frequent barriers to pre-hospital management of evolving acute illness. These findings suggest that implementing processes that encourage early patient-PCP communication and increase rates of prehospital management of infections and acute exacerbations of chronic diseases could reduce utilization of acute care services.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells - ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.
The study of human evolution is of interest to many both for the potential it has to improve our understanding of heritable disease, as well as for the possibility of illuminating evidence for adaptations that may help to tell the story of our origin. But uncovering evidence of positive selection at the genetic level has been a challenge. It remains unclear how much of the human genome has been affected by positive selection, what the main mechanism of selection is, and what types of patterns we should be looking for to identify adaptations. With whole-genome sequencing and high performance computation, we are quickly shifting to a field in which data is no longer a limiting factor. Here we will discuss the progress that has been made towards these ends, explore the best examples of human-specific adaptations to date, and discuss the implications of these findings within the context of classical population genetic theory.
Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis
The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic pathways in response to increased ceramide for sustenance of high energy demanding organ functions like the heart.
Regulation of eukaryotic gene transcription is often combinatorial in nature, with multiple transcription factors (TFs) regulating common target genes, often through direct or indirect mutual interactions. Many individual examples of cooperative binding by directly interacting TFs have been identified, but it remains unclear how pervasive this mechanism is during animal development. Cooperative TF binding should be manifest in genomic sequences as biased arrangements of TF-binding sites. Here, we explore the extent and diversity of such arrangements related to gene regulation during Drosophila embryogenesis. We used the DNA-binding specificities of 322 TFs along with chromatin accessibility information to identify enriched spacing and orientation patterns of TF-binding site pairs. We developed a new statistical approach for this task, specifically designed to accurately assess inter-site spacing biases while accounting for the phenomenon of homotypic site clustering commonly observed in developmental regulatory regions. We observed a large number of short-range distance preferences between TF-binding site pairs, including examples where the preference depends on the relative orientation of the binding sites. To test whether these binding site patterns reflect physical interactions between the corresponding TFs, we analyzed 27 TF pairs whose binding sites exhibited short distance preferences. In vitro protein-protein binding experiments revealed that >65% of these TF pairs can directly interact with each other. For five pairs, we further demonstrate that they bind cooperatively to DNA if both sites are present with the preferred spacing. This study demonstrates how DNA-binding motifs can be used to produce a comprehensive map of sequence signatures for different mechanisms of combinatorial TF action.
Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleo-cytoplasmic shuttling
The X-linked gene Rnf12 encodes the ubiquitin ligase RLIM/Rnf12 which serves as a major sex-specific epigenetic regulator of female mouse nurturing tissues. Early during embryogenesis, RLIM/Rnf12 expressed from the maternal allele is crucial for the development of extraembryonic trophoblast cells. In contrast, in mammary glands of pregnant and lactating adult females RLIM/Rnf12 expressed from the paternal allele functions as a critical survival factor for milk producing alveolar cells. While RLIM/Rnf12 is detected mostly in the nucleus, little is known about how and in which cellular compartment(s) RLIM/Rnf12 mediates its biological functions. Here, we demonstrate that RLIM/Rnf12 protein shuttles between the nucleus and cytoplasm and that this is regulated by phosphorylation of serine S214 located within its nuclear localization sequence (NLS). We show that shuttling is important for RLIM to exert its biological functions, as alveolar cell survival activity is inhibited in shuttling-deficient nuclear or cytoplasmic RLIM/Rnf12. Thus, the regulated nucleo-cytoplasmic shuttling of RLIM/Rnf12 coordinates cellular compartments during alveolar cell survival.
Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis
Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.
Accurate identification of polyadenylation sites from 3' end deep sequencing using a naive Bayes classifier
MOTIVATION: 3' end processing is important for transcription termination, mRNA stability and regulation of gene expression. To identify 3' ends, most techniques use an oligo-dT primer to construct deep sequencing libraries. However, this approach can lead to identification of artifactual polyadenylation sites due to internal priming in homopolymeric stretches of adenines. Although heuristic filters have been applied in these cases, they typically result in a high proportion of both false-positive and -negative classifications. Therefore, there is a need to develop improved algorithms to better identify mis-priming events in oligo-dT primed sequences.
RESULTS: By analyzing sequence features flanking 3' ends derived from oligo-dT-based sequencing, we developed a naive Bayes classifier to classify them as true or false/internally primed. The resulting algorithm is highly accurate, outperforms previous heuristic filters and facilitates identification of novel polyadenylation sites.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Epigenetic regulation and interactions between transcription factors and regulatory genomic regions play crucial roles in controlling transcriptional regulatory networks that drive development, environmental responses, and disease. Chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIP-seq) and ChIP followed by genomic tiling microarray hybridization (ChIP-chip) are the two of the most widely used technologies for genome-wide identification of DNA protein interactions and histone modification in vivo. Many algorithms and tools have been developed and evaluated that allow identification of transcription factor binding sites from ChIP-seq or ChIP-chip datasets. However, binding site identification is only the first step; the ultimate goal is to discover the regulatory network of the transcription factor (TF). Here, we present a common workflow for downstream analysis of ChIP-chip and ChIP-seq with an emphasis on annotating binding sites and integration with gene expression data to identify direct and indirect targets of the TF. These tools will help with the overall goal of unraveling transcriptional regulatory networks using datasets publicly available in GEO.
As sequencing technology continues to produce better quality genomes at decreasing costs, there has been a recent surge in the variety of data that we are now able to analyze. This is particularly true with regards to our understanding of the human genome—where the last decade has seen data advances in primate epigenomics, ancient hominid genomics, and a proliferation of human polymorphism data from multiple populations. In order to utilize such data however, it has become critical to develop increasingly sophisticated tools spanning both bioinformatics and statistical inference. In population genetics particularly, new statistical approaches for analyzing population data are constantly being developed—unfortunately, often without proper model testing and evaluation of type-I and type-II error. Because the common Wright-Fisher assumptions underlying such models are generally violated in natural populations, this statistical testing is critical. Thus, my dissertation has two distinct but related themes: 1) evaluating methods of statistical inference in population genetics, and 2) utilizing these methods to analyze the evolutionary history of humans and our closest relatives. The resulting collection of work has not only provided important biological insights (including some of the first strong evidence of selection on human-specific epigenetic modifications (Shulha, Crisci, Reshetov, Tushir et al. 2012, PLoS Bio), and a characterization of human-specific genetic changes distinguishing modern humans from Neanderthals (Crisci et al. 2011, GBE)), but also important insights in to the performance of population genetic methodologies which will motivate the future development of improved approaches for statistical inference (Crisci et al, in review).
US Trends in Quality-Adjusted Life Expectancy From 1987 to 2008: Combining National Surveys to More Broadly Track the Health of the Nation
Objectives. We used data from multiple national health surveys to systematically track the health of the US adult population.
Methods. We estimated trends in quality-adjusted life expectancy (QALE) from 1987 to 2008 by using national mortality data combined with data on symptoms and impairments from the National Medical Expenditure Survey (1987), National Health Interview Survey (1987, 1994-1995, 1996), Medical Expenditure Panel Survey (1992, 1996, 2000-2008), National Nursing Home Survey (1985, 1995, and 1999), and Medicare Current Beneficiary Survey (1992, 1994-2008). We decomposed QALE into changes in life expectancy, impairments, symptoms, and smoking and body mass index.
Results. Years of QALE increased overall and for all demographic groups-men, women, Whites, and Blacks-despite being slowed by increases in obesity and a rising prevalence of some symptoms and impairments. Overall QALE gains were large: 2.4 years at age 25 years and 1.7 years at age 65 years.
Conclusions. Understanding and consistently tracking the drivers of QALE change is central to informed policymaking. Harmonizing data from multiple national surveys is an important step in building this infrastructure. (Am J Public Health. Published online ahead of print September 12, 2013: e1-e10. doi:10.2105/AJPH.2013.301250).
Patients are often encountered clinically who have autism spectrum disorders (ASD) and also have symptoms suggestive of a comorbid psychotic disorder. A careful assessment for the presence of comorbid disorders is important. However, the core deficits seen in ASD, in social reciprocity, communication, and restricted behaviors and interests, can be mistaken for psychosis. Also, there is a subset of patients who present with a complex neurodevelopmental disorder with impairments that cross diagnostic categories. This article reviews the connections between ASD and psychosis, and highlights the key points to consider in patients who present with these "autism-plus" disorders.
Childhood trauma is a common occurrence and has been associated with psychosis and suggested as a risk factor leading to psychosis and schizophrenia in adulthood. This article introduces the scope of the problem and discusses the evidence for causal relationships between childhood adversities and increased risk for psychosis. The relationship between specific types of trauma and their association with specific psychotic symptoms is described, as well as the manifestations of co-occurring trauma effects and psychosis in adolescents. Clinical presentations and the use of diagnostic instruments, diagnostic comorbidities, and evidence-based psychotherapeutic interventions to treat effects of trauma in youth with psychotic illnesses are discussed.
Preface to the October 2013 issue of Child and Adolescent Psychiatric Clinics of North America. This issue was designed to help practicing child and adolescent psychiatrists and mental health providers become informed about the most recent scientific advances in this area of neuroscience, so that the providers feel more comfortable with identifying, assessing, and treating youth with psychosis.