ALBERT

Description: The variable pattern of complications seen among sickle cell disease patients is unlikely to be the result of solely the HBB glu6val mutation. Conventional case-control analyses using single nucleotide polymorphisms (SNPs) are useful in looking for single gene associations, however studying gene interactions becomes increasingly inefficient as the number of SNPs increase. Application of more complex statistical methods such as classification and regression trees (CART), stochastic gradient boosting (SGB) and Bayesian networks (Sebastiani et al, Nature Genet37: 435, 2005) allows for the analysis of many SNPs and covariates simultaneously. CART is a recursive partitioning method that develops a single tree-based model which is grown by creating “if-then” splitting rules which stratify patients into risk groups. The resulting over-fitted tree is then pruned to optimize size and classification and its predictive ability assessed using a test set or cross validation. SGB is a similar method, however, instead of one large tree many small trees are grown sequentially. Each new tree improves the quality of the model based upon the prior stage and is weighted based on its predictive ability. The final predicted value is computed by adding the weighted contribution of each small sub-tree and based on that value, a classification assigned. From the over 4,000 patients in the CSSCD, a subset of 1,353 were genotyped for 353 SNPs in over 160 genes that might impact the disease pathophysiology. Clinical data for these patients were merged with genotype data and 490 patients were identified who had at least one of the following vasoocclusive events: stroke, osteonecrosis of the humeral or femoral head and/or priapism. With the remaining patients serving as controls, CART and SGB was run on a random sample of 80% of the patients to identify genes and covariates whose interactions characterize patients with these vasoocclusive events and the accuracy assessed using the remaining patients as a test set. Along with age, sex and HbF, CART identified TGFBR3, SMAD9, CISH, KL and MAP3K71P1 as being associated with the vasoocclusive event phenotype and classified patients with a sensitivity of 34% and a specificity of 82%. SGB however, while identifying the same pattern of genes and covariates as being associated with vasoocclusive events, was able to classify patients with a sensitivity of 80% and a specificity of 68%. While CART provides a simple initial screening of genes and covariates that may be simultaneously associated with the phenotype, SGB provides a more accurate method of classification with higher sensitivity and similar specificity. Neither method requires the extensive model building of Bayesian networks. A more thorough understanding of the molecular mechanisms will lead to the ability to predict subphenotypes and improve their management.

Description: The phenotypic heterogeneity of sickle cell anemia (HbSS) is likely to be accounted for by multiple genetic modifiers. Priapism, a common vasoocclusive complication of HbSS, may reflect sickle vasculopathy. We hypothesized that the likelihood of developing priapism, and other vascular complications of sickle cell disease, may be influenced by genetic heterogeneity in genes that modulate inflammation, oxidant injury, nitric oxide (NO) biology, vasoregulation, cell-cell interaction and hemostasis. Accordingly, we studied patients with HbSS with or without coincident α thalassemia and examined the association of 129 single nucleotide polymorphisms (SNPs) in 44 candidate genes with priapism. One hundred forty-eight patients had at least one episode of priapism and were compared with 529 controls. Validated SNPs in the candidate genes were first selected from a public database. Genotypic counts were compared between cases and controls using multiple logistic regression. For each SNP, odds ratio (OR) and 95% confidence intervals (CI) were calculated. Pairwise linkage disequilibrium between each pair of SNP loci was evaluated by using a maximum likelihood method to infer phase for dual heterozygotes and was expressed as r2. In our first analysis, we considered a SNP to have an association with a phenotype when the p-value was equal to or less than 0.01, unless there was more than one SNP in a gene showing an association, when the p-value for significance was set at 0.05. When a SNP met these criteria, we further studied the gene with as many informative SNPs as possible. Haplotypes were reconstructed by using Bayesian methods as implemented in the PHASE package. A sliding window approach was used to assess evidence for association between haplotype and priapism. Patients with HbSS-α thalassemia were less likely to have priapism than patients with HbSS (p

Description: Fetal hemoglobin (HbF) inhibits the polymerization of sickle hemoglobin modulating some of the subphenotypes of sickle cell anemia. HbF concentrations vary considerably among patients and this variation is regulated as a multigenic trait; some regulatory regions previously identified are linked to the β-globin gene-like cluster and are also within quantitative trait loci (QTL) on chromosomes 6q, 8q and Xp. We genotyped panels of haplotype tagging (ht)SNPs in the β-globin gene-like cluster and covering the 8q and Xp QTL in two independent patient samples and applied two independent analytical methods to study their association with HbF levels. The first sample included 327 patients (135 htSNPs) and the second sample had 987 patients (102 htSNPs). Genotyping was done using a custom 384 multiplex design and the Illumina platform. Single SNP association was investigated by multiple linear regression analysis with simultaneous adjustment for age, sex and the co-existence of α thalassemia; we performed a permutation procedure to correct for multiple testing. The nonlinear regression Random Forest method was used for a joint analysis of covariates and all SNPs. In the smaller patient sample, 7 SNPs in TOX (thymus high mobility protein; 8q12.1) gene showed significant association with HbF (p-value

Description: In this work, the spatial extent of new particle formation (NPF) events and the relative probability of observing particles originating from different spatial origins around three rural sites in eastern China were investigated using the NanoMap method, using particle number size distribution (PNSD) data and air mass back trajectories. The length of the datasets used were 7, 1.5, and 3 years at rural sites Shangdianzi (SDZ) in the North China Plain (NCP), Mt. Tai (TS) in central eastern China, and Lin'an (LAN) in the Yangtze River Delta region in eastern China, respectively. Regional NPF events were observed to occur with the horizontal extent larger than 500 km at SDZ and TS, favoured by the fast transport of northwesterly air masses. At LAN, however, the spatial footprint of NPF events was mostly observed around the site within 100–200 km. Difference in the horizontal spatial distribution of new particle source areas at different sites was connected to typical meteorological conditions at the sites. Consecutive large-scale regional NPF events were observed at SDZ and TS simultaneously and were associated with a high surface pressure system dominating over this area. Simultaneous NPF events at SDZ and LAN were seldom observed. At SDZ the polluted air masses arriving over the NCP were associated with higher particle growth rate (GR) and new particle formation rate (J) than air masses from Inner Mongolia (IM). At TS the same phenomenon was observed for J, but GR was somewhat lower in air masses arriving over the NCP compared to those arriving from IM. The capability of NanoMap to capture the NPF occurrence probability depends on the length of the dataset of PNSD measurement but also on topography around the measurement site and typical air mass advection speed during NPF events. Thus the long-term measurements of PNSD in the planetary boundary layer are necessary in the further study of spatial extent and the probability of NPF events. The spatial extent, relative probability of occurrence, and typical evolution of PNSD during NPF events presented in this study provide valuable information to further understand the climate and air quality effects of new particle formation.

Description: Plasmaspheric hiss was observed by Van Allen Probe B in association with energetic electron injections in the outer plasmasphere. The energy of injected electrons coincides with the minimum resonant energy calculated for the observed hiss wave frequency. Interestingly, the variations in hiss wave intensity, electron flux and ultra low frequency (ULF) wave intensity exhibit remarkable correlations, while plasma density is not correlated with any of these parameters. Our study provides direct evidence for the first time that the injected anisotropic electron population, which is modulated by ULF waves, modulates the hiss intensity in the outer plasmasphere. This also implies that the plasmaspheric hiss observed by Van Allen Probe B in the outer plasmasphere (L 〉 ∼ 5.5) is locally amplified. Meanwhile, Van Allen Probe A observed hiss emission at lower L shells (

Description: The climatological variation of aerosol properties and the planetary boundary layer (PBL) during 2013–2015 over the Yangtze River Delta (YRD) region were investigated by employing ground-based Micro Pulse Lidar (MPL) and CE-318 sun-photometer observations. Combining Moderate Resolution Imaging Spectroradiometer (MODIS) and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellite products, enhanced haze pollution events affected by different types of aerosol over the YRD region were analyzed through vertical structures, spatial distributions, backward trajectories, and the potential source contribution function (PSCF) model. The results show that aerosols in the YRD are dominated by fine-mode particles, except in March. The aerosol optical depth (AOD) in June and September is higher due to high single scattering albedo (SSA) from hygroscopic growth, but it is lower in July and August due to wet deposition from precipitation. The PBL height (PBLH) is greater (means ranging from 1.23 to 1.84 km) and more variable in the warmer months of March to August, due to the stronger diurnal cycle and exchange of heat. Northern fine-mode pollutants are brought to the YRD at a height of 1.5 km. The SSA increases, blocking the radiation to the surface, and cooling the surface, thereby weakening turbulence, lowering the PBL, and in turn accelerating the accumulation of pollutants, creating a feedback to the cooling effect. Originated from the deserts in Xinjiang and Inner Mongolia, long-range transported dust masses are seen at heights of about 2 km over the YRD region with an SSA440 nm below 0.84, which heat air and raise the PBL, accelerating the diffusion of dust particles. Regional transport from biomass-burning spots to the south of the YRD region bring mixed aerosol particles at a height below 1.5 km, resulting in an SSA440 nm below 0.89. During the winter, the accumulation of the local emission layer is facilitated by stable weather conditions, staying within the PBL even below 0.5 km.

Description: Plasmaspheric hiss was observed by Van Allen Probe B in association with energetic electron injections in the outer plasmasphere. The energy of injected electrons coincides with the minimum resonant energy calculated for the observed hiss wave frequency. Interestingly, the variations of hiss wave intensity, electron flux, and ULF wave intensity exhibit remarkable correlations, while plasma density is not correlated with any of these parameters. Our study provides direct evidence for the first time that the injected anisotropic electron population, which is modulated by ULF waves, modulates the hiss intensity in the outer plasmasphere. This also implies that plasmaspheric hiss observed by Van Allen Probe B in the outer plasmasphere (L 〉 ~ 5.5) is locally amplified. Meanwhile, Van Allen Probe A observed hiss emission at lower L shells (

Description: In this work, the spatial extent of new particle formation (NPF) events and the relative probability of observing particles originating from different spatial origins around three rural sites in eastern China were investigated with the NanoMap method, using particle number size distribution (PNSD) data and air mass back trajectories. The length of the datasets used were 7-year, 1.5-year and 3-year at rural sites Shangdianzi (SDZ) in North China Plain (NCP), Mt. Tai (TS) in central eastern China, and Lin'an (LAN) in Yangtze River Delta region in eastern China, respectively. Regional NPF events were observed to occur with the horizontal extent larger than 500 km at SDZ and TS, favored by the fast transport of northwesterly air masses. At LAN, however, the spatial footprint of NPF events was mostly observed around the site within 100–200 km. Difference in the horizontal spatial distribution of new particle source areas at different sites was connected to typical meteorological conditions at the sites. Consecutive large-scale regional NPF events were observed at SDZ and TS simultaneously and were associated with a high surface pressure system dominating over this area. Simultaneous NPF events at SDZ and LAN were seldom observed. At SDZ the polluted air masses arriving over NCP were associated with higher particle growth rates (GR) and new particle formation rates (J) than air masses from Inner Mongolia (IM). At TS the same phenomenon was observed for J, but GR was somewhat lower in air masses arriving over NCP compared to those arriving from IM. The capability of NanoMap to capture the NPF occurrence probability depends on the length of the dataset of PNSD measurement, but also on topography around the measurement site and typical air mass advection speed during NPF events. Thus the long-term measurements of PNSD in planetary boundary layer are necessary in the further study on spatial extent and probability of NPF events. The spatial extent, relative probability of occurrence and typical evolution of PNSD during NPF event presented in this study provide valuable information to further understand the climate and air quality effect of new particle formation.

Description: The climatological variation of aerosol properties and the planetary boundary layer (PBL) during 2013–2015 over the Yangtze River Delta (YRD) region were investigated by employing ground-based Microwave Pulse Lidar (MPL) and CE-318 sun-photometer observations. Combining MODIS and CALIPSO satellite products, enhanced haze pollution events affected by different types of aerosol over the YRD region were analyzed through vertical structures, spatial distributions, backward trajectories, and the Potential Source Contribution Function (PSCF) model. The results show that aerosols in the YRD are dominated by fine-mode particles, except in March. The aerosol optical depth (AOD) in June and September is higher due to high single scattering albedo (SSA) from hygroscopic growth, but is lower in July and August due to wet deposition from precipitation. The PBL height (PBLH) is greater (means ranging from 1.23 to 1.84 km) and more variable in the warmer months of March to August, due to the stronger diurnal cycle and exchange of heat. Northern fine-mode pollutants are brought to the YRD at a height of 1.5 km. The SSA increases blocking the radiation to the surface, and cooling the surface, thereby weakening turbulence, lowering the PBL, and in turn accelerating the accumulation of pollutants, creating a feedback to the cooling effect. Originated from the deserts in Xinjiang and Inner Mongolia, long-range transported dust masses are seen at heights of about 2 km over the YRD region with an SSA440 nm below 0.84, which heat air and upraise PBL, accelerating the diffusion of dust particles. Regional transport from biomass burning spots to the south of the YRD region bring mixed aerosol particles at a height below 1.5 km, resulting in an SSA440 nm below 0.89. During the winter, the accumulation of local emission layer is facilitated by stable weather condition, staying within the PBL even below 0.5 km.

Description: This study analyzed the long-term variations in carbon monoxide (CO) mixing ratios from January 2006 to December 2017 at the Lin'an regional atmospheric background station (LAN; 30.3∘ N, 119.73∘ E, 138 m a.s.l.) in China's Yangtze River Delta (YRD) region. The CO mixing ratios were at their highest (0.69 ± 0.08 ppm) and lowest (0.54 ± 0.06 ppm) in winter and summer, respectively. The average daily variation in CO exhibited a double-peaked pattern, with peaks in the morning and evening and a valley in the afternoon. A significant downward trend of −11.3 ppb yr−1 of CO was observed from 2006 to 2017 at the LAN station, which was in accordance with the negative trends of the average CO mixing ratios and total column retrieved from the satellite data (Measurements of Pollution in the Troposphere, MOPITT) over the YRD region during the same period. The average annual CO mixing ratio at the LAN station in 2017 was 0.51 ± 0.04 ppm, which was significantly lower than that (0.71 ± 0.12 ppm) in 2006. The decrease in CO levels was largest in autumn (−15.7 ppb yr−1), followed by summer (−11.1 ppb yr−1), spring (−10.8 ppb yr−1), and winter (−9.7 ppb yr−1). Moreover, the CO levels under relatively polluted conditions (the annual 95th percentiles) declined even more rapidly (−22.4 ppb yr−1, r=-0.68, p