The Aerosol-Generating Effect Among Noninvasive Positive Pressure Ventilation, High-Flow Nasal Cannula, Nonrebreather Mask, Nasal Cannula, and Ventilator-Assisted Preoxygenation.

STUDY OBJECTIVE: To evaluate aerosol dispersion and exposure risk during oxygenation therapy among health care personnel. METHODS: This study compared the aerosol dispersion effect produced through continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), BiPAP with face coverings, a high-flow nasal cannula (HFNC) with face coverings, nasal cannula oxygenation (NCO) at 15 L/min with face coverings, nonrebreather mask (NRM), and ventilator-assisted preoxygenation (VAPOX) during oxygenation therapy at a minute ventilation of 10 L/min and 20 L/min. The length and width of aerosol dispersion were recorded, and aerosol concentrations were then detected at a mannequin's head, trunk, and feet. RESULTS: The average length dispersion distance of CPAP was 47.12 cm (SD, 12.56 cm), of BiPAP was 100.13 cm (SD, 6.03 cm), of BiPAP with face coverings was 62.20 cm (SD, 8.46 cm), of HFNC with face coverings was 67.09 cm (SD, 12.74 cm); of NCO with face coverings was 85.55 cm (SD, 7.28 cm); and of NRM was 63.08 cm (SD, 15.33 cm); VAPOX showed no visible dispersion. The aerosol concentrations at the feet under CPAP and at the head under BiPAP were significantly higher than those observed without an oxygen device. Compared with no oxygen device, the aerosol concentration with HFNC was higher at the mannequin's head, trunk, and feet; whereas it was lower with VAPOX and NRM. Moreover, when translated to the number of virus particles required to infect medical personnel (Nf), VAPOX took more time to achieve Nf than other devices. CONCLUSION: Strong flow from the oxygenation devices resulted in increased aerosol concentrations. CPAP at the feet side, BiPAP at the head side, HFNC, and NCO with face coverings significantly increase aerosol exposure and should be used with caution. Aerosol concentrations at all positions were lower with NRM and VAPOX.

Spatially varying effects of measured confounding variables on disease risk.

BACKGROUND: The presence of considerable spatial variability in incidence intensity suggests that risk factors are unevenly distributed in space and influence the geographical disease incidence distribution and pattern. As most human common diseases that challenge investigators are complex traits and as more factors associated with increased risk are discovered, statistical spatial models are needed that investigate geographical variability in the association between disease incidence and confounding variables and evaluate spatially varying effects on disease risk related to known or suspected risk factors. Information on geography that we focus on is geographical disease clusters of peak incidence and paucity of incidence. METHODS: We proposed and illustrated a statistical spatial model that incorporates information on known or hypothesized risk factors, previously detected geographical disease clusters of peak incidence and paucity of incidence, and their interactions as covariates into the framework of interaction regression models. The spatial scan statistic and the generalized map-based pattern recognition procedure that we recently developed were both considered for geographical disease cluster detection. The Freeman-Tukey transformation was applied to improve normality of distribution and approximately stabilize the variance in the model. We exemplified the proposed method by analyzing data on the spatial occurrence of sudden infant death syndrome (SIDS) with confounding variables of race and gender in North Carolina. RESULTS: The analysis revealed the presence of spatial variability in the association between SIDS incidence and race. We differentiated spatial effects of race on SIDS incidence among previously detected geographical disease clusters of peak incidence and incidence paucity and areas outside the geographical disease clusters, determined by the spatial scan statistic and the generalized map-based pattern recognition procedure. Our analysis showed the absence of spatial association between SIDS incidence and gender. CONCLUSION: The application to the SIDS incidence data demonstrates the ability of our proposed model to estimate spatially varying associations between disease incidence and confounding variables and distinguish spatially related risk factors from spatially constant ones, providing valuable inference for targeted environmental and epidemiological surveillance and management, risk stratification, and thorough etiologic studies of disease.

Differentiating anomalous disease intensity with confounding variables in space.

BACKGROUND: The investigation of perceived geographical disease clusters serves as a preliminary step that expedites subsequent etiological studies and analysis of epidemicity. With the identification of disease clusters of statistical significance, to determine whether or not the detected disease clusters can be explained by known or suspected risk factors is a logical next step. The models allowing for confounding variables permit the investigators to determine if some risk factors can explain the occurrence of geographical clustering of disease incidence and to investigate other hidden spatially related risk factors if there still exist geographical disease clusters, after adjusting for risk factors. METHODS: We propose to develop statistical methods for differentiating incidence intensity of geographical disease clusters of peak incidence and low incidence in a hierarchical manner, adjusted for confounding variables. The methods prioritize the areas with the highest or lowest incidence anomalies and are designed to recognize hierarchical (in intensity) disease clusters of respectively high-risk areas and low-risk areas within close geographic proximity on a map, with the adjustment for known or suspected risk factors. The data on spatial occurrence of sudden infant death syndrome with a confounding variable of race in North Carolina counties were analyzed, using the proposed methods. RESULTS: The proposed Poisson model appears better than the one based on SMR, particularly at facilitating discrimination between the 13 counties with no cases. Our study showed that the difference in racial distribution of live births explained, to a large extent, the 3 previously identified hierarchical high-intensity clusters, and a small region of 4 mutually adjacent counties with the higher race-adjusted rates, which was hidden previously, emerged in the southwest, indicating that unobserved spatially related risk factors may cause the elevated risk. We also showed that a large geographical cluster with the low race-adjusted rates, which was hidden previously, emerged in the mid-east. CONCLUSION: With the information on hierarchy in adjusted intensity levels, epidemiologists and public health officials can better prioritize the regions with the highest rates for thorough etiologic studies, seeking hidden spatially related risk factors and precisely moving resources to areas with genuine highest abnormalities.

Recognizing spatial and temporal clustering patterns of dengue outbreaks in Taiwan.

BACKGROUND: Dengue fever is the most common arboviral infection in humans, with viral transmissions occurring in more than 100 countries in tropical regions. A global strategy for dengue prevention and control was established more than 10 years ago. However, the factors that drive the transmission of the dengue virus and subsequent viral infection continue unabated. The largest dengue outbreaks in Taiwan since World War II occurred in two recent successive years: 2014 and 2015. METHODS: We performed a systematic analysis to detect and recognize spatial and temporal clustering patterns of dengue incidence in geographical areas of Taiwan, using the map-based pattern recognition procedure and scan test. Our aim was to recognize geographical heterogeneity patterns of varying dengue incidence intensity and detect hierarchical incidence intensity clusters. RESULTS: Using the map-based pattern recognition procedure, we identified and delineated two separate hierarchical dengue incidence intensity clusters that comprise multiple mutually adjacent geographical units with high dengue incidence rates. We also found that that dengue incidence tends to peak simultaneously and homogeneously among the neighboring geographic units with high rates in the same cluster. CONCLUSION: Beyond significance testing, this study is particularly desired by and useful for health authorities who require optimal characteristics of disease incidence patterns on maps and over time. Among the integrated components for effective prevention and control of dengue and dengue hemorrhagic fever are active surveillance and community-based integrated mosquito control, for which this study provides valuable inferences. Effective dengue prevention and control programs in Taiwan are critical, and have the added benefit of controlling the potential emergence of Zika.

Qualification and Verification of Serological Biomarker Candidates for Lung Adenocarcinoma by Targeted Mass Spectrometry.

Lung cancer is the leading cause of cancer mortality worldwide. Although many biomarkers have been identified for lung cancer, their low specificity and sensitivity present an urgent need for the identification of more candidate biomarkers. In this study, we conducted MRM-based targeted analysis to evaluate the potential utility of a list of candidate proteins for lung cancer diagnosis. A total of 1249 transitions of 420 peptides representing 102 candidate proteins from our previous study and the literature were first screened by MRM analysis in pooled plasma samples, resulting in 78 proteins remaining in the list. Relative quantification of these 78 proteins was further performed in 60 individual plasma samples from lung adenocarcinoma patients in stages I-III and matched healthy control subjects. Ultimately, nine proteins were found to be able to distinguish patients from controls. Further combinations of five, three, and two candidate marker proteins improved the sensitivity to discriminate patients from controls and resulted in a merged AUC value of nearly 1.00 in stages I-III patients versus controls. Our results highlighted several possible markers for lung adenocarcinoma, and the proposed protein panels require further validation in a larger cohort to evaluate their potential use in clinical applications or development of therapeutics.

Whole-genome detection of disease-associated deletions or excess homozygosity in a case-control study of rheumatoid arthritis.

Unlike genome-wide association studies, few comprehensive studies of copy number variation's contribution to complex human disease susceptibility have been performed. Copy number variations are abundant in humans and represent one of the least well-studied classes of genetic variants; in addition, known rheumatoid arthritis susceptibility loci explain only a portion of familial clustering. Therefore, we performed a genome-wide study of association between deletion or excess homozygosity and rheumatoid arthritis using high-density 550 K SNP genotype data from a genome-wide association study. We used a genome-wide statistical method that we recently developed to test each contiguous SNP locus between 868 cases and 1194 controls to detect excess homozygosity or deletion variants that influence susceptibility. Our method is designed to detect statistically significant evidence of deletions or homozygosity at individual SNPs for SNP-by-SNP analyses and to combine the information among neighboring SNPs for cluster analyses. In addition to successfully detecting the known deletion variants on major histocompatibility complex, we identified 4.3 and 28 kb clusters on chromosomes 10p and 13q, respectively, which were significant at a Bonferroni-type-corrected 0.05 nominal significant level. Independently, we performed analyses using PennCNV, an algorithm for identifying and cataloging copy numbers for individuals based on a hidden Markov model, and identified cases and controls that had chromosomal segments with copy number <2. Using Fisher's exact test for comparing the numbers of cases and controls with copy number <2 per SNP, we identified 26 significant SNPs (protective; more controls than cases) aggregating on chromosome 14 with P-values <10(-8).

An Approach to Identifying Spatial Variability in Observed Infectious Disease Spread in a Prospective Time-Space Series with Applications to COVID-19 and Dengue Incidence.

Most of the growing prospective analytic methods in space-time disease surveillance and intended functions of disease surveillance systems focus on earlier detection of disease outbreaks, disease clusters, or increased incidence. The spread of the virus such as SARS-CoV-2 has not been spatially and temporally uniform in an outbreak. With the identification of an infectious disease outbreak, recognizing and evaluating anomalies (excess and decline) of disease incidence spread at the time of occurrence during the course of an outbreak is a logical next step. We propose and formulate a hypergeometric probability model that investigates anomalies of infectious disease incidence spread at the time of occurrence in the timeline for many geographically described populations (e.g., hospitals, towns, counties) in an ongoing daily monitoring process. It is structured to determine whether the incidence grows or declines more rapidly in a region on the single current day or the most recent few days compared to the occurrence of the incidence during the previous few days relative to elsewhere in the surveillance period. The new method uses a time-varying baseline risk model, accounting for regularly (e.g., daily) updated information on disease incidence at the time of occurrence, and evaluates the probability of the deviation of particular frequencies to be attributed to sampling fluctuations, accounting for the unequal variances of the rates due to different population bases in geographical units. We attempt to present and illustrate a new model to advance the investigation of anomalies of infectious disease incidence spread by analyzing subsamples of spatiotemporal disease surveillance data from Taiwan on dengue and COVID-19 incidence which are mosquito-borne and contagious infectious diseases, respectively. Efficient R programs for computation are available to implement the two approximate formulae of the hypergeometric probability model for large numbers of events.

Continuous aerosol monitoring and comparison of aerosol exposure based on smoke dispersion distance and concentrations during oxygenation therapy.

This study evaluated the aerosol exposure risks while using common noninvasive oxygenation devices. A simulated mannequin was designed to breathe at a minute ventilation of 20 L/min and used the following oxygen-therapy devices: nasal cannula oxygenation (NCO) at 4 and 15 L/min, nonrebreathing mask (NRM) at 15 L/min, simple mask at 6 L/min, combination of NCO at 15 L/min and NRM at 15 L/min, high-flow nasal cannula (HFNC) at 50 L/min, and flush rate NRM. Two-dimension of the dispersion distance and the aerosol concentrations were measured at head, trunk, and foot around the mannequin for over 10 min. HFNC and flush-rate NRM yielded the longest dispersion distance and highest aerosol concentrations over the three sites of the mannequin than the other oxygenation devices and should use with caution. For flow rates of < 15 L/min, oxygenation devices with mask-like effects, such as NRM or NCO with NRM, decreased aerosol dispersion more effectively than NCO alone or a simple mask. In the upright position, the foot area exhibited the highest aerosol concentration regardless of the oxygenation device than the head-trunk areas of the mannequin. Healthcare workers should be alert even at the foot side of the patient while administering oxygenation therapy.

A comparative analysis of aerosol exposure and prevention strategies in bystander, pre-hospital, and inpatient cardiopulmonary resuscitation using simulation manikins.

To evaluate aerosol exposure risk and prevention strategies during bystander, pre-hospital, and inpatient cardiopulmonary resuscitation (CPR). This study compared hands-only CPR, CPR with a surgical or N95 mask, and CPR with a non-rebreather mask at 15 L/min. 30:2 compression-ventilation ratio CPR was tested with face-mask ventilation (FMV), FMV with a high efficiency particulate air (HEPA) filter; supraglottic airway (SGA), SGA with a surgical mask, SGA with a HEPA filter, or SGA with both. Continuous CPR was tested with an endotracheal tube (ET), ET with a surgical mask, a HEPA filter, or both. Aerosol concentration at the head, trunk, and feet of the mannequin were measured to evaluate exposure to CPR personnel. Hands-only CPR with a surgical or N95 face mask coverings and ET tube ventilation CPR with filters showed the lowest aerosol exposure among all study groups, including CPR with NRM oxygenation, FMV, and SGA ventilation. NRM had a mask effect and reduced aerosol exposure at the head, trunk, and feet of the mannequin. FMV with filters during 30:2 CPR reduced aerosol exposure at the head and trunk, but increased at the feet of the mannequin. A tightly-sealed SGA when used with a HEPA filter, reduced aerosol exposure by 21.00-63.14% compared with a loose-fitting one. Hands-only CPR with a proper fit surgical or N95 face mask coverings is as safe as ET tube ventilation CPR with filters, compared with CPR with NRM, FMV, and SGA. FMV or tight-sealed SGA ventilation with filters prolonged the duration to achieve estimated infective dose of SARS-CoV-2 2.4-2.5 times longer than hands-on CPR only. However, a loose-fitting SGA is not protective at all to chest compressor or health workers standing at the foot side of the victim, so should be used with caution even when using with HEPA filters.

Genetic susceptibility to patient-reported xerostomia among long-term oropharyngeal cancer survivors.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10-7; 5p13.2-p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10-6; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10-6; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10-5; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10-5; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10-5. Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10-5). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome characterized by early cancer onset, diverse tumor types, and multiple primary tumors. Germ-line TP53 mutations have been identified in most LFS families. A high-frequency single-nucleotide polymorphism, SNP309 (rs2279744), in MDM2 was recently confirmed to be a modifier of cancer risk in several case-series studies: substantially earlier cancer onset was observed in SNP309 G-allele carriers than in wild-type individuals by 7-16 years. However, cancer risk analyses that jointly account for measured hereditary TP53 mutations and MDM2 SNP309 have not been systematically investigated in familial cases. Here, we determined the combined effects of measured TP53 mutations, MDM2 SNP309, and gender and their interactions simultaneously in LFS families. We used the method that is designed for extended pedigrees and structured for age-specific risk models based on Cox proportional hazards regression. We analyzed the cancer incidence in 19 extended pedigrees with germ-line TP53 mutations ascertained through the clinical LFS phenotype. The dataset consisted of 463 individuals with 129 TP53 mutation carriers. Our analyses showed that the TP53 germ-line mutation and its interaction with gender were strongly associated with familial cancer incidence and that the association between MDM2 SNP309 and increased cancer risk was modest. In contrast with several case-series studies, the interaction between MDM2 SNP309 and TP53 mutation was not statistically significant in our LFS family cohort. Our results showed that SNP309 G-alleles were associated with accelerated tumor formation in both carriers and non-carriers of germ-line TP53 mutations.

Hemodynamic analysis of capillary in finger nail-fold using computational fluid dynamics and image estimation.

Red blood cell (RBC) dynamics in capillaries is a useful diagnostic tool for many diseases. Previous study showed that optical flow estimation (OFE) is capable of accurately calculating RBC velocities using image registration technique. The computational fluid dynamics (CFD) method is explored in this study to calculate the RBC velocity in capillaries of finger nail-fold for six cases. The two-dimensional capillary images were reconstructed to three-dimensional, assuming circular cross sections. The no-slip boundary conditions were applied on the vessel walls. The initial velocity of the RBC going into each capillary was calculated by OFE. The velocities of multiple points along each capillary calculated by CFD, V(CFD), were compared with OFE calculations, V(OFE). The calculated RBC velocity was in the range of 56-685µm/s. The average difference (V(CFD) - V(OFE)) with one standard deviation is -2.66±18.61µm/s for all the 48 calculation points, and 0.03±0.12µm/s for all except one points (47 points), indicating that CFD can provide a reasonable accuracy in RBC velocity calculation in finger nail-fold capillaries.

Accuracy evaluation of RBC velocity measurement in nail-fold capillaries.

Cutaneous red blood cell velocity in vivo can be measured by using capillaroscopy with image processing techniques. However, unlike simulated blood flow images, there is no standard to determine the accuracy of the techniques for computing blood flow velocities. In this paper, we quantitatively evaluated the accuracy of previously proposed optical flow method for measuring red blood cell velocity in nail-fold capillaries. Blood flow images of subjects under normal and occlusion-release conditions were examined by a capillaroscope. To obtain velocity values, the images were further analyzed by using optical flow, cross-correlation and visual inspection methods, respectively. Visual inspection method was taken as the golden standard to determine the accuracy of blood flow velocity measurement using optical flow and cross-correlation techniques. Results showed that optical flow estimation provided superior accuracy to cross-correlation when assessing real blood flow velocity in nail-fold capillaries. Optical flow estimation is able to measure red blood cell velocity with a high accuracy of 91% and 86% when the observed velocity is less than 0.5mm/s under normal and occlusion-release conditions, respectively. In addition, optical flow method showed good agreement with visual inspection in determining blood flow velocity in both normal and occlusion-release conditions when the high-velocity zone is excluded.

Comparing the effectiveness of negative-pressure barrier devices in providing air clearance to prevent aerosol transmission.

PURPOSE: To investigate the effectiveness of aerosol clearance using an aerosol box, aerosol bag, wall suction, and a high-efficiency particulate air (HEPA) filter evacuator to prevent aerosol transmission. METHODS: The flow field was visualized using three protective device settings (an aerosol box, and an aerosol bag with and without sealed working channels) and four suction settings (no suction, wall suction, and a HEPA filter evacuator at flow rates of 415 liters per minute [LPM] and 530 LPM). All 12 subgroups were compared with a no intervention group. The primary outcome, aerosol concentration, was measured at the head, trunk, and foot of a mannequin. RESULTS: The mean aerosol concentration was reduced at the head (p < 0.001) but increased at the feet (p = 0.005) with an aerosol box compared with no intervention. Non-sealed aerosol bags increased exposure at the head and trunk (both, p < 0.001). Sealed aerosol bags reduced aerosol concentration at the head, trunk, and foot of the mannequin (p < 0.001). A sealed aerosol bag alone, with wall suction, or with a HEPA filter evacuator reduced the aerosol concentration at the head by 7.15%, 36.61%, and 84.70%, respectively (99.9% confidence interval [CI]: -4.51-18.81, 27.48-45.73, and 78.99-90.40); trunk by 70.95%, 73.99%, and 91.59%, respectively (99.9% CI: 59.83-82.07, 52.64-95.33, and 87.51-95.66); and feet by 69.16%, 75.57%, and 92.30%, respectively (99.9% CI: 63.18-75.15, 69.76-81.37, and 88.18-96.42), compared with an aerosol box alone. CONCLUSIONS: As aerosols spread, an airtight container with sealed working channels is effective when combined with suction devices.

Effects of measured susceptibility genes on cancer risk in family studies.

Numerous family studies have been performed to assess the associations between cancer incidence and genetic and non-genetic risk factors and to quantitatively evaluate the cancer risk attributable to these factors. However, mathematical models that account for a measured hereditary susceptibility gene have not been fully explored in family studies. In this report, we proposed statistical approaches to precisely model a measured susceptibility gene fitted to family data and simultaneously determine the combined effects of individual risk factors and their interactions. Our approaches are structured for age-specific risk models based on Cox proportional hazards regression methods. They are useful for analyses of families and extended pedigrees in which measured risk genotypes are segregated within the family and are robust even when the genotypes are available only in some members of a family. We exemplified these methods by analyzing six extended pedigrees ascertained through soft-tissue sarcoma patients with p53 germ-line mutations. Our analyses showed that germ-line p53 mutations and sex had significant interaction effects on cancer risk. Our proposed methods in family studies are accurate and robust for assessing age-specific cancer risk attributable to a measured hereditary susceptibility gene, providing valuable inferences for genetic counseling and clinical management.

Experimental estimation of blood flow velocity through simulation of intravital microscopic imaging in micro-vessels by different image processing methods.

Quantization of red blood cell (RBC) velocity in micro-vessel is one of the techniques for dynamic observation of microvascular mechanisms. The flow measurement of RBC in micro-vessels is still a challenge nowadays. Image processing for velocity measurement using a frame by frame analysis is a common approach. The accuracy of the calculations, which is algorithm dependant, has rarely been examined. In this paper, we evaluated the accuracy of the existing methods, which includes cross correlation method, Hough transform method, and optical flow method, by applying these methods to simulated micro-vessel image sequences. Simulated experiments in various micro-vessels with random RBC motion were applied in the evaluation. The blood flow variation in the same micro-vessels with different RBC densities and velocities was considered in the simulations. The calculation accuracy of different flow patterns and vessel shapes were also examined, respectively. Based on the comparison, the use of an optical flow method, which is superior to a cross-correlation method or a Hough transform method, is proposed for measuring RBC velocity. The study indicated that the optical flow method is suitable for accurately measuring the velocity of the RBCs in small or large micro-vessels.

Detection of disease-associated deletions in case-control studies using SNP genotypes with application to rheumatoid arthritis.

Genomic deletions have long been known to play a causative role in microdeletion syndromes. Recent whole-genome genetic studies have shown that deletions can increase the risk for several psychiatric disorders, suggesting that genomic deletions play an important role in the genetic basis of complex traits. However, the association between genomic deletions and common, complex diseases has not yet been systematically investigated in gene mapping studies. Likelihood-based statistical methods for identifying disease-associated deletions have recently been developed for familial studies of parent-offspring trios. The purpose of this study is to develop statistical approaches for detecting genomic deletions associated with complex disease in case-control studies. Our methods are designed to be used with dense single nucleotide polymorphism (SNP) genotypes to detect deletions in large-scale or whole-genome genetic studies. As more and more SNP genotype data for genome-wide association studies become available, development of sophisticated statistical approaches will be needed that use these data. Our proposed statistical methods are designed to be used in SNP-by-SNP analyses and in cluster analyses based on combined evidence from multiple SNPs. We found that these methods are useful for detecting disease-associated deletions and are robust in the presence of linkage disequilibrium using simulated SNP data sets. Furthermore, we applied the proposed statistical methods to SNP genotype data of chromosome 6p for 868 rheumatoid arthritis patients and 1,197 controls from the North American Rheumatoid Arthritis Consortium. We detected disease-associated deletions within the region of human leukocyte antigen in which genomic deletions were previously discovered in rheumatoid arthritis patients.

Red blood cell velocity measurements of complete capillary in finger nail-fold using optical flow estimation.

A new approach for the measurement of the red blood cell (RBC) velocity from capillary video by using optical flow estimation has been developed. An image registration function based on mutual information was used for stabilizing images in order to cope with slight finger movement during video acquisition. After image alignment, a skeleton extraction algorithm implemented by thinning was followed which enabled tracking blood flow entirely in arteriolar and venular limbs, and the curved segment as well. Optical flow and cross-correlation approaches were applied individually for velocity estimation of twelve microcirculation videos acquired independently from three healthy volunteers. The RBC velocity of 12 vessels at three given measurement sites (arteriolar, curve and venular sites) in a 45-second period of occlusion-release condition of vessel were examined. There were four stages of flow conditions: resting (T(1)), pre-occlusion (T(2)), post-occlusion (T(3)) and release (T(4)). The results from both approaches revealed that the velocity difference among the three sites were not significant. The pattern of distribution of RBC velocity was also reported. The correlation coefficient (r) of the velocity calculated using optical flow and cross-correlation in four stages of blood flow conditions and the overall correlation were: 1-window: r(T1)=0.68, r(T2)=0.67, r(T3)=0.92, r(T4)=0.88 and r(All)=0.79; 2-window: r(T1)=0.84, r(T2)=0.88, r(T3)=0.87, r(T4)=0.93 and r(All)=0.88. The averaged velocity results showed no significant differences between optical flow and 2-window cross-correlation in all flow conditions. Optical flow estimation is not only independent to the direction of flow, but also able to calculate the intensity displacement of all pixels. The proposed velocity measurement system has been shown to provide complete velocity information for the whole vessel limb which demonstrates the advantage of measuring blood flow at the level of microcirculation more accurately.

Statistical methods for anomalous discrete time series based on minimum cell count.

Temporal incidence patterns of point epidemics often contain periods of unusually low or high frequencies. Identifying variations in incidence frequencies, which may be caused by changes in exposure to infectious or environmental agents, may provide important insights into the pathogenesis or etiology of a disease. We propose and formulate new statistical tests for temporal and space-time anomalies that are based on the minimum frequency in a unit of time and that are meaningful for the characteristic incidence patterns of the cases studied. Among the most widely applied methods are the Ederer-Myers-Mantel test, the Maxima test, and the scan test, which are all sensitive to the maximum frequency within a short period of time. We elucidate the importance and utility of our new tests and the existing tests and suggest a systematic statistical analysis of reported disease anomalies using these tests combined. Data on a temporal series of adolescent suicide from the US National Center for Health Statistics were analyzed using these methods.