Fellowship Cynthis Dickerson: Nonparametric Estimation of No-Observed Adverse Effect Levels (NOAELs) from a Set of Drug Studies - Ellagic Acid

Nonparametric statistics are statistics not based on parameterized families of probability distributions, like the normal distribution. They are important because is it common for data to follow a distribution other than a known one. The NOAEL ( No Observed Adverse Effect Level) is an important part of the non-clinical risk assessment for new drugs. It is the highest dose at which there was not an observed toxic or adverse effect. There are important theoretical limitations to the traditional NOAEL calculation, which led to the newer Benchmark Dose (BMD) method. QBEST represents a superior statistical method to the NOAEL and BMD methods for determining NOAEL. Chikungunya is a rapidly spreading mosquito-borne disease that now infects over 3 million people worldwide. Since 2013 it has spread throughout the Caribbean and has recently entered the United States. BSN476, a drug for treating chikungunya infections, contains in part ellagic acid. Ellagic acid is a polyphenolic compound with anti-proliferative and antiviral properties that produces 99.6% inhibition of Chikungunya virus in vitro at 10 uM. This project utilizes a novel statistical method designed for Big Data problems - the Quantile Bootstrap Error Statistical Test, or QBEST, to estimate the NOAEL of a drug to treat Chikungunya with 98% confidence from a set of small studies (published or unpublished). QBEST is a form of cluster discriminant analysis. QBEST works by analyzing clusters of dosages that caused an effect, and clusters of dosages that caused no effect (determined from the studies). Running a simulation in which each cluster is moved and adjusting for cluster skew enables QBEST to measure the distance between groups of studies in probability space, until it finds a NOAEL dosage for the entire population at a specified level of statistical significance (usually 95% or 98%). In this proposal, QBEST will be applied to the task of determining a safe level of ellagic acid for the first-in-human study of BSN476 in order to develop a treatment for the disease Chikungunya.