ALBERT

Description: Introduction: Limited data are available on combined parent and self-reported behavioral symptoms in long-term survivors of childhood acute lymphoblastic leukemia (ALL) after treatment with contemporary chemotherapy only protocols. This study evaluated associations between chemotherapy exposures, parent emotional distress and reported child behavioral and psychiatric symptoms in survivors enrolled on a single institutional protocol. Methods: Survivors of childhood ALL (n=162; 49.0% male; mean [SD] age 12.1[2.6] years; time since diagnosis 7.5[1.6] years), who were at least 5 years post diagnosis and between 8-17 years of age, self-reported behavioral symptoms (Conners' Rating Scale) during a long-term follow-up visit. Parent-report of child behavioral symptoms was collected (Behavior Assessment System for Children) during the same visit. Age- and sex-adjusted standard scores were calculated for both measures, with impairment defined as a symptom level above the 90th percentile compared to normative data. Parents also completed the Diagnostic Interview for Children and Adolescents to determine whether their child met clinical criteria for psychiatric disorders. The proportion of children meeting criteria was compared to reported frequencies in the general population. Exposures to high-dose IV methotrexate, number of intrathecal therapy doses (cytarabine, methotrexate and hydrocortisone), and age at diagnosis were analyzed with multivariable Poisson regression as predictors of child behavioral symptoms and psychiatric condition. Association of Parent education level with child outcomes was examined using univariate Poisson regression model. Parent emotional distress was assessed using the Brief Symptom Inventory 18 (BSI-18), and raw scores were converted into sex specific T-scores using national normative data. T-scores ≥ 63 were considered to represent clinically significant emotional distress. Symptoms of parent posttraumatic stress (PTS) were evaluated using the Impact of Event Scale-Revised (IES-R) and levels of stress were calculated for three subscales (thought intrusions, avoidance, and hyperarousal), consistent with PTS diagnostic criteria. Associations between parent- and self-reported symptoms in children with parent emotional distress and PTS were examined with Fisher's exact test. Results: Compared to the expected population frequency of 10%, significantly more survivors self-reported symptoms of inattention (27.7%), hyperactivity/impulsivity (25.8%) and oppositional behavior (20%), all p's

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: Stroke is a major vascular complication of sickle cell anemia, more frequent in patients under the age of 20 years. Transcranial Doppler (TCD) flow studies can predict the likelihood of stroke in children with sickle cell anemia, but only 10% of individuals with abnormal TCD values will have stroke, and stroke will occur in some individuals with normal TCD. Therefore, more precise means of prognosis would be welcome so that prophylactic treatments like transfusions or hydroxyurea can be targeted to individuals at highest risk. Using Bayesian networks (BNs), we analyzed 235 single nucleotide polymorphisms (SNPs) in 80 candidate genes in 1398 unrelated subjects with sickle cell anemia enrolled in the Cooperative Study of Sickle Cell Disease. Bayesian networks are a novel generation of multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. These modules can be learned from data and then can be used to describe how changes in some variables affect other variables and ultimately the risk for the phenotype of interest. Bayesian networks provide a coherent framework within which genotypes, phenotypes and environmental factors can be seamlessly integrated into a comprehensive genomic landscape. We found that 25 SNPs on 11 genes and 4 clinical variables - including α thalassemia and fetal hemoglobin - interact in a complex network of dependency to modulate the risk of stroke. This network of interactions includes three genes (TGFBR2, TGFBR3, BMP6) with a functional role in the TGF-beta pathway and one gene (SELP) already associated with stroke in the general population. We validated our results in a different population by predicting the occurrence of stroke in a set of 114 subjects not included in the original study: 7 stroke patients and 107 control patients, a proportion consistent with the phenotype distribution in the original cohort study. Our model predicted the correct outcome for all 7 stroke patients, and for 105 of 107 non-stroke patients, with 100% true positive rate and 98.14% true negative rate, and an overall predictive accuracy of 98.2%. Our results support the hypothesis that stroke in sickle cell anemia patients is a complex trait caused by the interaction of multiple genes, and the predictive accuracy of our model is a step toward the development of additional prognostic tests to allow us to more precisely identify sickle cell anemia patients at risk for stroke. The presence in our model of genes already associated with stroke, such as SELP, suggests that some genetic factors predisposing to stroke are shared by both sickle cell anemia patients and stroke victims in the general population, and that our model may offer some insights into the genetic basis of the third leading cause of death in the United States.

Description: Predicting a broad risk of selected serious vasoocclusive complications of sickle cell anemia is possible. For example, patients with higher hemoglobin concentrations are less likely to have a stroke. Yet, it has not been feasible to integrate the many clinical and laboratory abnormalities of sickle cell anemia into a predictive model that permits an understanding of the interactions among common clinical and laboratory abnormalities. From the database of the Cooperative Study of Sickle Cell Disease, we examined clinical and laboratory data from nearly 1500 individuals with sickle cell anemia, with or without coincident α thalassemia. We used these data to develop a Bayesian network that describes the interactions between clinical and laboratory data and their associations with the risk for complications of sickle cell anemia. Bayesian networks are multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. The modules can be learned from data using statistical techniques and can be used to describe how changes in some variables affect other variables and ultimately the risk for phenotypes of interest. Our model shows that a complex network of interactions between clinical and laboratory variables underlies common complications of sickle cell anemia and ultimately death. Particularly important is the protective role that α thalassemia appears to play in common complications of sickle cell anemia. For example, α thalassemia, by decreasing erythrocyte density, reduces hemolysis and is associated with lower levels of bilirubin and an associated decreased risk for priapism. Bilirubin levels may reflect nitric oxide (NO) availability and NO may be invoved in the etiology of priapism. α thalassemia is also associated with smaller numbers of reticulocytes that are strongly associated with a decreased risk for acute chest syndrome and osteonecrosis; and it is associated with higher level of fetal hemoglobin and a reduction in leukocyte counts with a significant decreased risk for stroke and death. This model can be used to predict the occurrence of certain complications of sickle cell anemia and early death, given the presence of other disease complications and variations among common laboratory variables. For example, our model predicts a 10% risk for stroke at early age and an 11% risk for early death in patients with sickle cell anemia without α thalassemia compared with a 4% risk for stroke and 1.5% risk for early death for individuals with coincident α thalassemia. However, the predictive power of this model is limited, and we conjecture that this is a reflection of the omission of the genotypic changes that underlie the phenotypes. In related work using this same patient population, we analyzed genetic polymorphisms in candidate genes and showed than 25 SNPs and 4 clinical variables, including α thalassemia and fetal hemoglobin, were associated with increased risk of stroke and that this model predicted the occurrence of stroke in 114 individuals in a different population with 98% accuracy. The lack of the same predictive power of our current model suggests that genetic variants play a fundamental role in susceptibility to stroke and other complications of sickle cell anemia.

Description: Background: Among youth with sickle cell disease (SCD), morbidity and mortality substantially increase following departure from pediatric care. Care continuity following transfer from pediatric to adult-centered care is paramount to ensure maintenance of health care delivery and reduce the risk of poor clinical outcomes. The American Academy of Pediatrics recommends matriculation in adult care within 6 months from leaving pediatric care for patients with special health care needs. Failure to transition from pediatric to adult care among youth with SCD may contribute to frequent disease complications and early death. No formal analysis has been conducted to quantify the risk of care interruption as youth transition from pediatric to adult care on the rate of acute health care utilization. We tested the hypothesis that patients who interrupted care for more than 6 months as they moved from the pediatric to the adult-centered care setting would have higher frequency of acute health care utilization. Methods: With IRB approval, we conducted a retrospective review of the rate of acute care utilization among patients with SCD who were transitioned from the pediatric sickle cell program at St. Jude Children's Research Hospital to the adult sickle cell program at Methodist University Hospital, Memphis TN between January 2014 and December 2017. We compared the rates of emergency department (ED) and inpatient utilization among those who established care 〉6 months from completing pediatric care (interrupted care continuity) and those who established adult care within 6 months from completing pediatric care (uninterrupted care continuity). We used person-time rates to compare the rates of emergency department and inpatient encounters per patient between the two care continuity groups. Results: Between January 2014 and December 2017 there were 172 patients with SCD who completed pediatric care and established adult care: 63 of them had a latency time from pediatric to adult care 〉6 months and 109 had a latency time from pediatric to adult care ≤6 months. Their follow-up since matriculation in adult care was 2245 and 2197 person-years for interrupted and uninterrupted care continuity groups, respectively The median (range) age upon establishing adult care was 20 (range, 20 to 24) years and 18 (range, 18 to 19) years for the interrupted and uninterrupted care continuity groups, respectively. Patients who interrupted care 〉6 months after leaving pediatric care had an incidence rate of 0.18 ED visits/person-year compared to 0.09 ED visits/person-year among those who completed the first visit within 6 months from leaving pediatric care (IRR 0.48, 95%CI 0.40-0.57, p6 months after leaving pediatric care had an incidence rate of 0.09 inpatient visits/person-year compared to 0.04 inpatient visits/person-year among those who completed the first visit within 6 months from leaving pediatric care (IRR 0.42 (95%CI 0.32-0.54, p

Description: Non-typhoidal Salmonella (NTS) infection (salmonellosis) is one of the most prevalent gastrointestinal diseases throughout the world. Human infections caused by Salmonella Newport, Javiana, and Mississippi serotypes have been observed to occur at higher rates on an annual basis in western Tennessee. The reason for the increased rate of NTS infection by these three serotypes in this region is not known. We conducted a case-case analysis to identify potential risk factors associated with the three Salmonella serotypes using FoodNet data, obtained from the Tennessee Department of Health, consisting of 1578 culture-confirmed salmonellosis cases in Tennessee from 2013 through 2015. Among all the exposure variables tested (254 in total), we found contact with pet treats or chews in the seven days prior to illness was the factor that was significantly associated with these serotypes compared to other serotypes (odds ratio adjusted = 3.0 (95% confidence intervals 1.6, 5.5), P 〈 0.0005). This study highlights the need for further investigation of potential exposures (other than pet treats or chews), including several possible environmental sources of NTS infection in humans.