Faculty Bibliography

We propose and study a simple and innovative non-parametric approach to estimate the age-of-onset distribution for a disease from a cross-sectional sample of the population that includes individuals with prevalent disease. First, we estimate the joint distribution of two event times, the age of disease onset and the survival time after disease onset. We accommodate that individuals had to be alive at the time of the study by conditioning on their survival until the age at sampling. We propose a computationally efficient expectation-maximization (EM) algorithm and derive the asymptotic properties of the resulting estimates. From these joint probabilities we then obtain non-parametric estimates of the age-at-onset distribution by marginalizing over the survival time after disease onset to death. The method accommodates categorical covariates and can be used to obtain unbiased estimates of the covariate distribution in the source population. We show in simulations that our method performs well in finite samples even under large amounts of truncation for prevalent cases. We apply the proposed method to data from female participants in the Washington Ashkenazi Study to estimate the age-at-onset distribution of breast cancer associated with carrying BRCA1 or BRCA2 mutations.

BACKGROUND:The hand is highly visible and contributes to an individual's aesthetic image and perceived age. Current perspectives on hand aesthetics are primarily based on expert opinion rather than on lay population perspectives, which are less understood. Our study explores general population perceptions on the features that contribute most to an attractive hand. METHODS:Participants rated the attractiveness of 20 standardized hands as well as the appearance based on each characteristic: freckles, hair presence, skin tone, wrinkles, vein appearance, and soft tissue volume. The relative importance of each feature was assessed by comparison with overall attractiveness scores through multivariate analysis of variance. RESULTS:A total of 223 participants completed the survey. Soft tissue volume ( r = 0.73) was most strongly correlated with overall attractiveness, followed by wrinkles ( r = 0.71), skin tone consistency ( r = 0.69), veins ( r = 0.65), freckles ( r = 0.61), and hair ( r = 0.47). Female hands were perceived as more attractive, with a mean rating of 4.7 of 10, compared with 4.4 in males ( P < 0.001). Participants correctly identified the gender of 90.4% of male hands and 65.0% of female hands. Age was strongly inversely correlated with attractiveness ( r = -0.80). CONCLUSIONS:Soft tissue volume is the most important factor in lay perception of hand aesthetics. Female and younger hands were perceived as more attractive. Hand rejuvenation may be optimized by prioritizing soft tissue volume with filler or fat grafting, with secondary priority on resurfacing to address skin tone and wrinkling. An understanding of the factors most important to patients in aesthetic appearance is critical to achieving a pleasing result.

OBJECTIVES/UNASSIGNED:The high frequency of chemotherapy resistance is ultimately responsible for clinical relapse in acute lymphoblastic leukemia (ALL). Nevertheless, the molecular mechanism relevant to glucocorticoid (GC) resistance remains ambiguous. METHODS/UNASSIGNED:Quantitative real-time polymerase chain reaction and Western blot were performed to detect the expressions of paraoxonase 2 (PON2), Bcl-2 and Bax. shRNA was used to knockdown PON2 expression in SUP-B15 and REH cell. CCK-8 and flow cytometry assay were conducted to monitor the changes of proliferation and apoptosis in ALL cells. The growth of ALL REH cells in vivo was determined using transplanted tumor model. RESULTS/UNASSIGNED:This study was designed to identify GC resistance-associated genes by means of the transcriptome chip from the public Gene Expression Omnibus database, and preliminarily investigation of dexamethasone (DEX)-resistance mechanism in ALL. We disclosed that PON2 expression was elevated in ALL patients and especially higher in DEX-resistance ALL patients. Then, cell apoptosis assay suggested that silencing of PON2 dramatically promoted in DEX-resistant ALL cells apoptosis and the activity of Caspase 3 induced by DEX administration. In xenograft tumor model, PON2 knockdown significantly reduced DEX-resistant ALL cells growth in immunodeficient mice. CONCLUSIONS/UNASSIGNED:Collectively, inhibition of PON2 may represent a novel method to restore the sensitivity of treatment-resistant ALL to GC-induced cell death.

Typically, case-control studies to estimate odds-ratios associating risk factors with disease incidence only include newly diagnosed cases. Recently proposed methods allow incorporating information on prevalent cases, individuals who survived from disease diagnosis to sampling, into cross-sectionally sampled case-control studies under parametric assumptions for the survival time after diagnosis. Here we propose and study methods to additionally use prospectively observed survival times from prevalent and incident cases to adjust logistic models for the time between diagnosis and sampling, the backward time, for prevalent cases. This adjustment yields unbiased odds-ratio estimates from case-control studies that include prevalent cases. We propose a computationally simple two-step generalized method-of-moments estimation procedure. First, we estimate the survival distribution assuming a semiparametric Cox model using an expectation-maximization algorithm that yields fully efficient estimates and accommodates left truncation for prevalent cases and right censoring. Then, we use the estimated survival distribution in an extension of the logistic model to three groups (controls, incident, and prevalent cases), to adjust for the survival bias in prevalent cases. In simulations, under modest amounts of censoring, odds-ratios from the two-step procedure were equally efficient as those estimated from a joint logistic and survival data likelihood under parametric assumptions. This indicates that utilizing the cases' prospective survival data lessens model dependencies and improves precision of association estimates for case-control studies with prevalent cases. We illustrate the methods by estimating associations between single nucleotide polymorphisms and breast cancer risk using controls, and incident and prevalent cases sampled from the US Radiologic Technologists Study cohort.

BACKGROUND:Distal radius fractures represent some of the most common injuries to the upper extremity, yet current evidence demonstrates great variability in the management of this injury. Elderly patients, in particular, stand to benefit from the early mobilization provided by operative fixation with a volar bearing plate. METHODS:We conducted a retrospective chart review on all patients 65 years or older who underwent unilateral open reduction internal fixation of distal radius fractures using a volar bearing plate at a single institution between January 2014 and January 2016. We excluded patients with bilateral injuries, multiple fractures, and major injuries to the same extremity. RESULTS:Fifty-five patients met criteria for this study. By AO classification, we repaired 17 type A, 24 type B, and 14 type C fractures. At final radiographic measurements, average radial height compared with ulna measured -0.31 mm, average radial inclination measured 20.45 degrees, and average volar tilt measured 7.11 degrees. On discharge, 36 patients had wrist range-of-motion data consistent with a functional wrist. Four patients had limitations in the flexion/extension plane, 8 with radial-ulnar deviation, and 7 had limitations in both planes. CONCLUSIONS:Distal radius fractures in the elderly may successfully be treated with a volar bearing plate. Useful strategies include supraperiosteal dissection of the radius from the pronator quadratus, use of a longer plate for stronger proximal fixation in osteoporotic bone, and regional block. This methodology allows for a safe procedure facilitating the early return of hand and wrist function.

Ganglioglioma is a rare central nervous system neoplasm representing 0.4% to 1.7% of all brain tumors and most frequently occurs in the pediatric population with an incidence of 7.6%. These tumors are usually slow-growing and well-circumscribed solid or cystic lesions. Gangliogliomatosis infrequently occurs in the frontal lobe, pineal gland, basal ganglia, hypothalamus, and optic chiasm, with very few reports of brainstem ganglioglioma. We report a case of a 35-year-old female who initially presented with headache, vertigo, ataxia, saccadic dysfunction, dysarthria, and dysmetria for several years due to an unknown etiology. Her brain imaging showed multiple lesions in the pons and the cerebellum with cystic changes and size reduction and enlargement over the next few years while her neurological symptoms continued to worsen. The patient received courses of steroid treatment that improved her neurological symptoms, suggesting an inflammatory component of her disease. Extensive workup for an inflammatory or infectious etiology was unfruitful and two brain biopsies were inconclusive. A third biopsy showed atypical glial nuclei, binucleated cells, and Rosenthal fibers and the presence of BRAF V600E mutation was detected. The diagnosis of gangliogliomatosis was consequently established. This case illustrates that gangliogliomatosis may present with the waxing-and-waning neurological signs and symptoms. It can masquerade inflammatory processes in the central nervous system on brain imaging and deserves careful consideration in the diagnosis of patients with an indolent course of neurological deterioration.