Charles W. Goss

The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results

Purpose:Evaluation of the clinician’s role in the optimal interpretation of clinical exome sequencing (ES) results.Methods:Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results.Results:The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. Clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases.Conclusions:Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of postanalytical diagnostic work-up in solving the “diagnostic odyssey.” Genet Med advance online publication 02 March 2017

Effects of Obesity and Hypertension on Pulse Wave Velocity in Children

Pulse wave velocity (PWV) is a biomarker of arterial stiffness. Findings from prior studies are conflicting regarding the impact of obesity on PWV in children. The authors measured carotid‐femoral PWV in 159 children aged 4 to 18 years, of whom 95 were healthy, 25 were obese, 15 had hypertension (HTN), and 24 were both obese and hypertensive. Mean PWV increased with age but did not differ by race or sex. In adjusted analyses in children 10 years and older (n=102), PWV was significantly higher in children with hypertension (PWV±standard deviation, 4.9±0.7 m/s), obesity (5.0±0.9 m/s), and combined obesity‐hypertension (5.2±0.6 m/s) vs healthy children (4.3±0.7 m/s) (each group, P<.001 vs control). In our study, obesity and HTN both significantly and independently increased PWV, while African American children did not have a higher PWV than Caucasian children.

Ureteral Stent Placement and Immediate Graft Function are associated with Increased Risk of BK Viremia in the First Year after Kidney Transplantation

Ureteral stent (UrSt) placement has been shown to be a significant independent risk factor for BK viruria, viremia, and BK virus nephropathy. We assessed whether this observation could be validated at our high volume kidney transplant center that has had a strong historical focus on BK virus nephropathy detection. We performed a retrospective case–control study of adults receiving a kidney‐only transplant and followed for 1 year between 2004 and 2011 with uniform immunosuppression and use of blood BK virus PCR screening protocol. Among 1147 patients, 443 (38.6%) received a UrSt and 17.2% with a UrSt had BK viremia versus 13.5% without stent (odds ratio 1.33; 95% CI: 1.00–1.78). We confirmed a previously reported association between immediate graft function (IGF) and higher rate of BK viremia (15.7% vs. 5.9% in patients without IGF). On multivariable competing risks Cox regression in patients with IGF, UrSt (adjusted hazard ratio [aHR] 1.35; 95% CI: 1.04–1.75) and African American race (aHR 1.47; 95% CI: 1.04–2.09) significantly increased the risk for BK viremia. In the largest sample size to date, we confirmed that UrSt placement during kidney transplant surgery is a risk factor for BK viremia within the first year post‐transplant and that IGF is associated with BK viremia.

Comprehensive Assessment of a Hotspot with Persistent Bancroftian Filariasis in Coastal Sri Lanka

Abstract. The Sri Lankan Anti-Filariasis campaign distributed five rounds of mass drug administration (MDA with diethylcarbamazine plus albendazole) to some 10 million people in eight districts between 2002 and 2006. Sri Lanka was recognized by the WHO for having eliminated lymphatic filariasis (LF) as a public health problem in 2016. However, recent studies by our group documented pockets with persistent LF in coastal Sri Lanka, especially in Galle district. The present study was performed to reexamine an area previously identified as a potential hotspot for persistent LF (Balapitiya Public Health Inspector area, population 17,500). A community survey documented high rates for circulating filarial antigenemia (3%, confidence interval [CI]: 1.8–4.9) and microfilaremia (1%, CI: 0.5–2.5%). Circulating filarial antigenemia rates were 2.8-fold higher in males than females. High prevalence was also observed for anti-filarial antibodies in young children (5.7%, CI: 3.7–8.4%) and for filarial DNA in vector mosquitoes (5.2%, CI: 4.2–6.3%). Spatial data showed that persistent LF was dispersed across the entire study area. Other studies showed that persistent LF was not limited to Balapitiya and not solved by additional rounds of MDA. Molecular xenomonitoring studies conducted in 2016 in 22 of 168 Public Health Midwife areas in the coastal Galle evaluation unit (approximate population 600,000) found that 179 of 660 (27%) pools of Culex collected from all areas were positive for Wuchereria bancrofti DNA by quantitative polymerase chain reaction; the estimated infection rate in mosquitoes was 1.26%, CI: 1.0–1.5%. Interventions other than routine MDA will be required to remove LF hotspots in Balapitiya and in other areas in coastal Sri Lanka.

End-stage renal disease after pediatric heart transplantation: A 25-year national cohort study

BACKGROUND End-stage renal disease (ESRD), defined as the need for chronic dialysis and/or kidney transplantation (KTx), is a known complication after heart transplant (HTx). However, factors associated with ESRD are not well elucidated. The objectives of this study were to determine the prevalence, risk factors, and outcomes associated with ESRD after pediatric HTx. METHODS Scientific Registry of Transplant Recipients data were linked, using direct identifiers, to the United States Renal Data System to identify patients (aged ≤ 18 years) who underwent primary HTx between 1989 and 2013. Risk factors for ESRD and death were analyzed using Cox regression analysis. RESULTS Combining the above 2 databases identified ~25% additional HTx patients who developed ESRD that were not captured by either database alone. During a median follow-up of 11.8 years, ESRD developed in 276 of 6,901 patients (4%). The actuarial risk of developing ESRD after HTx was 3% at 10 years and 16% at 20 years. Age at HTx > 1 year, African-American race, year of HTx before 2000, hypertension, diabetes mellitus, re-HTx, acute dialysis, graft failure, and hospitalized infection were significant risk factors for ESRD development. Those who remained on chronic dialysis had higher risk of death than those who received KTx (hazard ratio, 31.4; 95% confidence interval, 20.8-48.4; p < 0.0001). CONCLUSIONS ESRD after pediatric HTx is more prevalent in HTx survivors than documented by a transplant database alone. A number of factors develop at or after HTx that increase the risk for developing ESRD. Use of KTx in post-HTx ESRD is associated with improved survival.

Using the newer Kidney Disease: Improving Global Outcomes criteria, beta-2-microglobulin levels associate with severity of acute kidney injury

ABSTRACT Beta-2-microglobulin (B2M) is a marker of proximal tubular injury and glomerular filtration. Analyses using older/non-standardized definitions have shown low efficacy of B2M to predict acute kidney injury (AKI). We assessed if elevated levels of B2M would associate with either the diagnosis of AKI [under current Kidney Disease: Improving Global Outcomes (KDIGO) criteria] or recovery from AKI. We performed a retrospective study, including children who had urine B2M (uB2M) and/or serum B2M (sB2M) measured by immunoturbidimetry in our clinical laboratory between January 2011 and December 2015. We defined AKI based on KDIGO criteria [increase of serum creatinine (sCr) 0.3 mg/dL over 48 h or >50% baseline over 7 days] or urine output <0.5 mL/kg/h for 24 h. Recovery from AKI was defined as a return to baseline sCr within 6 months. We calculated receiver operating characteristics (ROC) area under the curve (AUC). Of 529 patients, 245 developed AKI. Serum and uB2M associated with AKI development (AUCs 0.84 and 0.73, respectively). Patients had a graded higher median sB2M and uB2M with each higher AKI stage. sB2M differentiated Stage I from Stage III AKI (P < 0.001) and Stage II from Stage III AKI (P = 0.004). However, neither uB2M nor sB2M levels associated with recovery from AKI. Only older age {hazard ratio [HR] 0.97, [95% confidence interval (CI) 0.94–0.99]} and need for dialysis [HR 0.39 (95% CI 0.23–0.61)] predicted incomplete recovery after AKI. Using KDIGO criteria, sB2M and uB2M associate with the severity of AKI. Given its relative ease and lower cost, we suggest more widespread use of B2M for AKI detection.

Effect of Frequent Dialysis on Renal Recovery: Results From the Acute Renal Failure Trial Network Study

Introduction The optimal frequency of intermittent hemodialysis (IHD) in the treatment of acute kidney injury (AKI) remains unclear. Increasing the frequency of IHD, while offering the possible advantage of reduced ultrafiltration requirement and less hemodynamic instability per session, amplifies patient contact with an extracorporeal circuit with possible deleterious cardiovascular and immunological consequences. A recent study suggested that intensive renal replacement therapy (RRT) is associated with a decrease in urine output during AKI. We hypothesized that increased frequency of IHD may be associated with delayed renal recovery. Methods This is a post hoc analysis of the Acute Renal Failure Trial Network (ATN) study. The ATN study was a large randomized multicenter trial of intensive versus less-intensive RRT in critically ill patients with AKI. This study used either continuous RRT or IHD, depending on the hemodynamic status of the patient. Of 1124 patients, 246 were treated solely with IHD during the study period and were included in this analysis. The participants were randomized to receive IHD 3 days per week (L-IntRRT) or 6 days per week (IntRRT). The primary outcome of interest was renal recovery at day 28. Results L-IntRRT was associated with higher number of RRT-free days through day 28 than IntRRT (mean difference 2.5 days; 95% confidence interval [CI]: −4.79 to −0.27 days; P = 0.028). The likelihood for renal recovery at day 28 was lower in the IntRRT group (OR: 0.49; 95% CI: 0.28–0.87; P = 0.016). Conclusion In hemodynamically stable patients with AKI, intensifying the frequency of IHD from 3 to 6 days per week may be associated with impaired renal recovery.