High regularities in eye-movement patterns reveal the dynamics of the visual working memory allocation mechanism.

With only two to five slots of visual working memory (VWM), humans are able to quickly solve complex visual problems to near optimal solutions. To explain the paradox between tightly constrained VWM and impressively complex human visual problem-solving ability, we propose several principles for dynamic VWM allocation. In particular, we propose that complex visual information is represented in a temporal manner using only a few slots of VWM that include global and local visual chunks. We built a model of human traveling salesman problem solving based on these principles of VWM allocation and tested the model with eye-movement data. Exactly as the model predicted, human eye movements during traveling salesman problem solving have precise quantitative regularities with regard to both the general statistical pattern of attentional fixations and how they vary across individuals with different VWM capacities. Even though VWM capacity is very limited, eye movements dynamically allocate VWM resources to both local and global information, enabling attention to fine details without loss of the big picture.

Measuring the effect of commuting on the performance of the Bayesian Aerosol Release Detector.

BACKGROUND: Early detection of outdoor aerosol releases of anthrax is an important problem. The Bayesian Aerosol Release Detector (BARD) is a system for detecting releases of aerosolized anthrax and characterizing them in terms of location, time and quantity. Modelling a population's exposure to aerosolized anthrax poses a number of challenges. A major difficulty is to accurately estimate the exposure level--the number of inhaled anthrax spores--of each individual in the exposed region. Partly, this difficulty stems from the lack of fine-grained data about the population under surveillance. To cope with this challenge, nearly all anthrax biosurveillance systems, including BARD, ignore the mobility of the population and assume that exposure to anthrax would occur at one's home administrative unit--an assumption that limits the fidelity of the model. METHODS: We employed commuting data provided by the U.S. Census Bureau to parameterize a commuting model. Then, we developed methods for integrating commuting into BARD's simulation and detection algorithms and conducted two studies to measure the effect. The first study (simulation study) was designed to assess how BARD's detection and characterization performance are impacted by incorporation of commuting in BARD's outbreak-simulation algorithm. The second study (detection study) was designed to measure the effect of incorporating commuting in BARD's outbreak-detection algorithm. RESULTS: We found that failing to account for commuting in detection (when commuting is present in simulation) leads to a deterioration in BARD's detection and characterization performance that is both statistically and practically significant. We found that a simplified approach to accounting for commuting in detection--simplified to maintain tractability of inference--nearly fully restored both detection and characterization performance of BARD detector. CONCLUSION: We conclude that it is important to account for commuting (and mobility in general) in BARD's simulation algorithm. Further, the proposed method for incorporating commuting in BARD's detection algorithm can successfully perform the necessary correction in the detection algorithm, while preserving BARD's practicality. In our future work, we intend to further study the problem of the trade-off between running time and accuracy of the computation in BARD's version that includes commuting and ultimately find the best such trade-off.

Mining aggregates of over-the-counter products for syndromic surveillance.

There has recently been a surge of research efforts aimed at very early detection of disease outbreaks. An important strategy for improving the timeliness of outbreak detection is to identify signals that occur early in the epidemic process. We have developed a novel algorithm to identify aggregates of "similar" over-the-counter products that have strong association with a given disease. This paper discusses the proposed algorithm and reports the results of an evaluation experiment. The experimental results show that this algorithm holds promise for discovering product aggregates with outbreak detection performance that is superior to that of predefined categories. We also found that the products extracted by the proposed algorithm were more strongly correlated with the disease data than the standard predefined product categories, while also being more strongly correlated with each other than the products in any predefined category.

Template-driven spatial-temporal outbreak simulation for outbreak detection evaluation.

We developed a non-disease specific template-driven spatial-temporal outbreak simulator for evaluating outbreak detection algorithms. With only a few outbreak parameter settings, our simulator can generate different patterns of outbreak cases either temporally or spatial-temporally using three different generation algorithms: deterministic, independent, Poisson process. Our simulator is flexible, easy to implement and provides case event times rather than aggregated counts. We provide examples of outbreak simulations using linear template functions. Our Template-Driven Simulator is a useful tool for evaluating of outbreak detection algorithms.

The Bayesian aerosol release detector: an algorithm for detecting and characterizing outbreaks caused by an atmospheric release of Bacillus anthracis.

Early detection and characterization of outdoor aerosol releases of Bacillus anthracis is an important problem. As health departments and other government agencies address this problem with newer methods of surveillance such as environmental surveillance through the BioWatch program and enhanced medical surveillance, they increasingly have newer types of surveillance data available. However, existing methods for the statistical analysis of surveillance data do not account for recent meteorological conditions, as human analysts did in the case of the Sverdlovsk anthrax outbreak of 1979 to determine whether the locations of victims were consistent with meteorological conditions in the week preceding their onset of illness. This paper describes the Bayesian aerosol release detector (BARD), an algorithm that analyzes both medical surveillance data and meteorological data for early detection and characterization of outdoor releases of B. anthracis. It estimates a posterior distribution over the location, quantity, and date and time conditioned on a release having occurred. We report a proof-of-concept evaluation of BARD, which demonstrates that the approach shows promise and warrants further development and evaluation.

Unsupervised clustering of over-the-counter healthcare products into product categories.

A general problem in biosurveillance is finding appropriate aggregates of elemental data to monitor for the detection of disease outbreaks. We developed an unsupervised clustering algorithm for aggregating over-the-counter healthcare (OTC) products into categories. This algorithm employs MCMC over hundreds of parameters in a Bayesian model to place products into clusters. Despite the high dimensionality, it still performs fast on hundreds of time series. The procedure was able to uncover a clinically significant distinction between OTC products intended for the treatment of allergy and OTC products intended for the treatment of cough, cold, and influenza symptoms.

High-fidelity injection detectability experiments: a tool for evaluating syndromic surveillance systems.

INTRODUCTION: When public health surveillance systems are evaluated, CDC recommends that the expected sensitivity, specificity, and timeliness of surveillance systems be characterized for outbreaks of different sizes, etiologies, and geographic or demographic scopes. High-Fidelity Injection Detectability Experiments (HiFIDE) is a tool that health departments can use to compute these metrics for detection algorithms and surveillance data that they are using in their surveillance system. OBJECTIVE: The objective of this study is to develop a tool that allows health departments to estimate the expected sensitivity, specificity, and timeliness of outbreak detection. METHODS: HiFIDE extends existing semisynthetic injection methods by replacing geometrically shaped injects with injects derived from surveillance data collected during real outbreaks. These injects maintain the known relation between outbreak size and effect on surveillance data, which allows inferences to be made regarding the smallest outbreak that can be expected to be detectable. RESULTS: An example illustrates the use of HiFIDE to analyze detectability of a waterborne Cryptosporidium outbreak in Washington, DC. CONCLUSION: HiFIDE enables public health departments to perform system validations recommended by CDC. HiFIDE can be obtained for no charge for noncommercial use (http://www.hifide.org).

An evaluation of three policies for updating product categories in the National Retail Data Monitor.

A problem in biosurveillance is how frequently to update controlled vocabularies that identify various data elements such as laboratory tests and over-the-counter healthcare products. More frequent updates improve completeness of data captured over time, but introduction of new codes into a surveillance system may cause false alarms when codes are aggregated into analytic categories. We studied the effect of three policies for updating UPCs, the controlled vocabulary for over-the-counter healthcare products used by the National Retail Data Monitor. To compare different policies for updating, we analyzed historical data from two cities for the 18 product categories of the National Retail Data Monitor under annual, quarterly, or monthly UPC update policies. We measured the effect on data completeness and false alarm rate. We found that the monthly update policy had the highest data completeness and led to the fewest number of additional false alarms. Overall, monthly updating of UPCs was the superior policy.

A multivariate procedure for identifying correlations between diagnoses and over-the-counter products from historical datasets.

A general problem in biosurveillance is finding the optimal aggregates of more basic data to monitor for the detection of disease outbreaks. We developed a multivariate procedure for identifying the set of over-the-counter (OTC) healthcare products that correlates best with a set of diagnoses. To ensure that the procedure produces results that agree with clinical knowledge of diseases and (OTC) products, we applied it to a set of products and set of diagnoses for which the correlation was known to be high. Our hypothesis was that the model could achieve parsimony in the set of diagnoses that correlate with sales of pediatric electrolytes while still producing a high correlation. The procedure narrowed the set of diagnoses that correlate with pediatric electrolytes from 51 diagnoses to eight diagnoses. The correlation of the set of 51 diagnoses with electrolyte sales was 0.95 and the correlation of the set of 8 diagnoses with electrolytes was 0.96. We conclude that the procedure functions as intended and is suitable for further testing with other problems in finding optimal aggregates of OTC products, and more generally of other types of biosurveillance data, to monitor for the detection of various disease outbreaks.

Issue a boil-water advisory or wait for definitive information? A decision analysis.

OBJECTIVE: Study the decision to issue a boil-water advisory in response to a spike in sales of diarrhea remedies or wait 72 hours for the results of definitive testing of water and people. METHODS: Decision analysis. RESULTS: In the base-case analysis, the optimal decision is test-and-wait. If the cost of issuing a boil-water advisory is less than 13.92 cents per person per day, the optimal decision is to issue the boil-water advisory immediately. CONCLUSIONS: Decisions based on surveillance data that are suggestive but not conclusive about the existence of a disease outbreak can be modeled.

Automatic correction of ocular artifacts in the EEG: a comparison of regression-based and component-based methods.

A variety of procedures have been proposed to correct ocular artifacts in the electroencephalogram (EEG), including methods based on regression, principal components analysis (PCA) and independent component analysis (ICA). The current study compared these three methods, and it evaluated a modified regression approach using Bayesian adaptive regression splines to filter the electrooculogram (EOG) before computing correction factors. We applied each artifact correction procedure to real and simulated EEG data of varying epoch lengths and then quantified the impact of correction on spectral parameters of the EEG. We found that the adaptive filter improved regression-based artifact correction. An automated PCA method effectively reduced ocular artifacts and resulted in minimal spectral distortion, whereas ICA correction appeared to distort power between 5 and 20 Hz. In general, reducing the epoch length improved the accuracy of estimating spectral power in the alpha (7.5-12.5 Hz) and beta (12.5-19.5 Hz) bands, but it worsened the accuracy for power in the theta (3.5-7.5 Hz) band and distorted time domain features. Results supported the use of regression-based and PCA-based ocular artifact correction and suggested a need for further studies examining possible spectral distortion from ICA-based correction procedures.

Computer-identified nuclear localization signal in exon 1A of the transporter DMT1 is essentially ineffective in nuclear targeting.

Divalent metal transporter 1 (DMT1; also called DCT1, Nramp2, or SLC11A2) has multiple isoforms that localize differently in many cell types. DMT1 +IRE species (encoded by mRNA with an iron-responsive element) are limited to the plasma membrane and cytosolic vesicles. In neural cells, -IRE isoforms of DMT1 (encoded by mRNA lacking an IRE) localize to the nucleus, plasma membrane, and cytosolic vesicles. In considering nuclear compartmentalization of -IRE isoforms, we hypothesized that the newly identified exon 1A in the N-terminus of this transporter might contain a nuclear localization signal. DNA constructs starting with exon 1A and ending with exons encoding alternative isoforms were made and transiently transfected into HEK293T and PC12 cells as well as rat sympathetic neurons. None of the constructs appeared in the nucleus despite the presence of exon 1A. Antibody specific for exon 1A was also used in both immunostaining and Western blots to investigate localization of exon 1A expressed both endogenously and ectopically in cells. Again, nuclear localization of DMT1 containing exon 1A was not observed. Our data suggest that exon 1A is neither sufficient nor necessary for DMT1 to appear in the nucleus.

Delayed presentation of traumatic rupture of the diaphragm.

Ruptured diaphragm as a result of blunt trauma can present acutely or late in the disease, process. Late presentation is often a result of herniation of abdominal contents into the thorax. Patients may present with nonspecific symptoms, and may complain of chest pain, abdominal pain, dyspnea, tachypnea, or cough. Clinicians must have a high index of suspicion for prompt diagnosis. Diagnostic tools include chest radiograph, CT scan, and MRI. The treatment for rupture of the diaphragm is surgical. The authors report a case of traumatic rupture of the diaphragm presenting 20 years after an automobile accident with blunt trauma to the abdomen.

Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat.

Iron accumulation in the brain occurs in a number of neurodegenerative diseases. Two new iron transport proteins have been identified that may help elucidate the mechanism of abnormal iron accumulation. The Divalent Metal Transporter 1 (DMT1), is responsible for iron uptake from the gut and transport from endosomes. The Metal Transport Protein 1 (MTP1) promotes iron export. In this study we determined the cellular and regional expression of these two transporters in the brains of normal adult and Belgrade rats. Belgrade rats have a defect in DMT1 that is associated with lower levels of iron in the brain. In the normal rat, DMT1 expression is highest in neurons in the striatum, cerebellum, thalamus, ependymal cells lining the third ventricle, and vascular cells throughout the brain. The staining in the ependymal cells and endothelial cells suggests that DMT1 has an important role in iron transport into the brain. In Belgrade rats, there is generalized decrease in immunodetectable DMT1 compared to normal rats except in the ependymal cells. This decrease in immunoreactivity, however, was absent on immunoblots. The immunoblot analysis indicates that this protein did not upregulate to compensate for the chronic defect in iron transport. MTP1 staining is found in most brain regions. MTP1 expression in the brain is robust in pyramidal neurons of the cerebral cortex but is not detected in the vascular endothelial cells and ependymal cells. MTP1 staining in Belgrade rats was decreased compared to normal, but similar to DMT1 this decrease was not corroborated by immunoblotting. These results indicate that DMT1 and MTP1 are involved in brain iron transport and this involvement is regionally and cellularly specific.

Cellular distribution of iron in the brain of the Belgrade rat.

In this study, we investigated the cellular distribution of iron in the brain of Belgrade rats. These rats have a mutation in Divalent Metal Transporter 1, which has been implicated in iron transport from endosomes. The Belgrade rats have iron-positive pyramidal neurons, but these are fewer in number and less intensely stained than in controls. In the white matter, iron is normally present in patches of intensely iron-stained oligodendrocytes and myelin, but there is dramatically less iron staining in the Belgrade rat. Those oligodendrocytes that stained for iron did so strongly and were associated with blood vessels. Astrocytic iron staining was seen in the cerebral cortex for both normal rats and Belgrade rats, but the iron-stained astrocytes were less numerous in the mutants. Iron staining in tanycytes, modified astrocytes coursing from the third ventricle to the hypothalamus, was not affected in the Belgrade rat, but was affected by diet. The results of this study indicate that Divalent Metal Transporter 1 is important to iron transport in the brain. Iron is essential in the brain for basic metabolic processes such as heme formation, neurotransmitter production and ATP synthesis. Excess brain iron is associated with a number of common neurodegenerative diseases. Consequently, elucidating the mechanisms of brain iron delivery is critical for understanding the role of iron in pathological conditions.

Evidence for and consequences of chronic heme deficiency in Belgrade rat reticulocytes.

The Belgrade rat has a microcytic, hypochromic anemia inherited as an autosomal recessive trait (gene symbol b). Transferrin-dependent iron uptake is defective because of a mutation in Nramp2 (now DMT1, also called DCT1), the protein responsible for endosomal iron efflux. Hence, Belgrade reticulocytes are iron deficient. We show that a chromatographic method is able to measure the amount of 'free' heme in reticulocytes. Most of the 'free' heme is the result of biosynthesis. Succinylacetone, an inhibitor of heme synthesis, decreases the level of 'free' heme and cycloheximide, an inhibitor of globin synthesis, increases the 'free' heme level. In a pulse-chase experiment with 59Fe-transferrin, the 'free' heme pool behaves as an intermediate, with a half-life of just over 2 h. Belgrade reticulocytes contain about 40% as much 'free' heme as do heterozygous or homozygous reticulocytes. This deficiency of 'free' heme slows initiation of translation in Belgrade reticulocytes by increasing the level of an inhibitor of initiation. Thus the Belgrade rat makes a whole animal model available with chronic heme deficiency.

Non-transferrin-bound iron uptake in Belgrade and normal rat erythroid cells.

Belgrade (b) rats have an autosomal recessive, microcytic, hypochromic anemia. Transferrin (Tf)-dependent iron uptake is defective because of a mutation in DMT1 (Nramp2), blocking endosomal iron efflux. This experiment of nature permits the present study to address whether the mutation also affects non-Tf-bound iron (NTBI) uptake and to use NTBI uptake compared to Tf-Fe utilization to increase understanding of the phenotype of the b mutation. The distribution of 59Fe2+ into intact erythroid cells and cytosolic, stromal, heme, and nonheme fractions was different after NTBI uptake vs. Tf-Fe uptake, with the former exhibiting less iron into heme but more into stromal and nonheme fractions. Both reticulocytes and erythrocytes exhibit NTBI uptake. Only reticulocytes had heme incorporation after NTBI uptake. Properly normalized, incorporation into b/b heme was approximately 20% of +/b, a decrease similar to that for Tf-Fe utilization. NTBI uptake into heme was inhibited by bafilomycin A1, concanamycin, NH4Cl, or chloroquine, consistent with the endosomal location of the transporter; cellular uptake was uninhibited. NTBI uptake was unaffected after removal of Tf receptors by Pronase or depletion of endogenous Tf. Concentration dependence revealed that NTBI uptake into cells, cytosol, stroma, and the nonheme fraction had an apparent low affinity for iron; heme incorporation behaved like a high-affinity process, as did an expression assay for DMT1. DMT1 serves in both apparent high-affinity NTBI membrane transport and the exit of iron from the endosome during Tf delivery of iron in rat reticulocytes; the low-affinity membrane transporter, however, exhibits little dependence on DMT1.

Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.

The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption. The b reticulocyte defect appears to be failure of iron transport out of endosomes within the transferrin cycle. Aspects of this phenotype are similar to those reported for the microcytic anemia (mk) mutation in the mouse. Recently, mk has been attributed to a missense mutation in the gene encoding the putative iron transporter protein Nramp2. To investigate the possibility that Nramp2 was also mutated in the b rat, we established linkage of the phenotype to the centromeric portion of rat chromosome 7. This region exhibits synteny to the chromosomal location of Nramp2 in the mouse. A polymorphism within the rat Nramp2 gene cosegregated with the b phenotype. A glycine-to-arginine missense mutation (G185R) was present in the b Nramp2 gene, but not in the normal allele. Strikingly, this amino acid alteration is the same as that seen in the mk mouse. Functional studies of the protein encoded by the b allele of rat Nramp2 demonstrated that the mutation disrupted iron transport. These results confirm the hypothesis that Nramp2 is the protein defective in the Belgrade rat and raise the possibility that the phenotype shared by mk and b animals is unique to the G185R mutation. Furthermore, the phenotypic characteristics of these animals indicate that Nramp2 is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome.

Iron supplementation moderates but does not cure the Belgrade anemia.

Belgrade rats inherit microcytic, hypochromic anemia as an autosomal recessive trait (gene symbol b). Erythrocytes and tissue are iron deficient in the face of elevated TIBC (total iron binding capacity) and percent iron saturation; iron injections increased the number of erythrocytes but their appearance remained abnormal. We have investigated iron supplements to improve husbandry of b/b rats and to learn more about the underlying defect and its tissue distribution. Weekly i.m. (intramuscular) injections of iron-dextran (Imferon at 30 mg kg-1) improved the anemia but did not alter the red cell morphology. Certain diets also improved the health of b/b rats when compared to standard rat chows by the criteria of weight, survival to adulthood, hematology and reproduction. The critical nutritional factor turned out to be iron bioavailability, with ferrous iron added to the diet improving the health of Belgrade rats without affecting the underlying erythroid defect. Tissue iron measurements after dietary or parenteral supplementation confirmed the iron deficient status of untreated b/b rats and established that dietary ferrous iron partially relieved this deficiency, with injections leading to greater amounts of tissue iron. Serum iron and TIBC were also found to be elevated in untreated b/b rats, with dietary supplementation decreasing but not eliminating the elevation in TIBC. These studies indicate that iron supplements can improve the health of b/b rats without altering the underlying defect and also suggest that the mutation could alter iron uptake in the GI (gastrointestinal) tract.

Transferrin and the transferrin cycle in Belgrade rat reticulocytes.

Belgrade rats have an autosomal recessive anemia with hypochromia and microcytosis. Iron uptake into reticulocytes is approximately 20% of normal, but transferrin uptake is unimpaired. We have systematically compared the transferrin cycle in Belgrade versus normal reticulocytes to locate the defect more precisely. Belgrade transferrin was functionally normal as purified transferrin or whole plasma. Transferrin affinity of Belgrade receptors was indistinguishable from normal, but Belgrade reticulocytes had twice as many receptors. Belgrade transferrin endocytosis was 1.5 times faster than normal, whereas exocytosis is about twice as fast. Initially Belgrade reticulocytes internalize iron at an unimpaired rate, but they lag behind normal by 5 min. During reincubation, they release 25-33% of iron taken up during a 30-min preincubation, whereas normal cells do not lose a detectable fraction. Unexpectedly, transferrin cycle time was unchanged. Hence another kinetic step of the cycle is slower, compensating for increases in Belgrade endocytosis and exocytosis. After one cycle, Belgrade reticulocytes retain only half of the iron that entered, but over 90% of iron entering normal cells remains within. Iron unloading is ineffective inside the Belgrade vesicle; 85% of iron that entered on transferrin returned to the medium after exocytosis, whereas only 45% of iron entering normal reticulocytes exits. Ineffective utilization of iron in or near Belgrade endosomes accounts for the Belgrade defect.