Analyzing high dimensional data based on hypothesis testing for assessing similarity between complex organic molecules using mass spectrometry
A technology of organic molecules and hypothesis testing, which is applied to the analysis of materials, material inspection products, chemical data mining, etc.
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Embodiment 1
[0028] Sample Preparation
[0029] Copolymer-1 (20 mg, available from Sigma-Aldrich (St.Louis, MO)) or GA (20 mg, ScinoPharm Taiwan Ltd.) was dissolved in 1 mL of mannitol (40 mg / mL) at the same concentration as Kepasone, And seven replicate samples of copolymer-1 or GA were prepared from 30 μL of the solution. 10 samples were prepared from each batch of 30 μL Kepasone. For digestion, 45 μL of distilled deionized water (ddH 2 O), 18 μL of ammonium bicarbonate (24 mg / mL, adjusted to pH 8.40), and 15 μL of Lys-C (0.2 g / L). These samples were incubated in a 37°C water bath for 16 hours. After incubation, 10 μL of trifluoroacetic acid (0.1%, v / v) and 118 μL of acetonitrile (100%) were added to stop the reaction. These samples were filtered through a hydrophilic polyvinylidene fluoride membrane filter (Millipore, Billerica, MA) with a pore size of 0.22 μm. Samples were stored at -20°C prior to UPLC-MS analysis.
Embodiment 2
[0031] High-dimensional LC-MS data generated from copolymer-1 samples
[0032] LC / MS data from 7 replicate samples from 2 different sources of the Copolymer-1 run, including a Copolymer-1 sample and a negative control (NC), both of which appear to be similar ( Figure 1a Copolymer-1 sample and 1b negative control), which indicated greater reproducibility between their individual 7 replicates. Comparing the LC-MS data of the copolymer-1 sample and 10 batches of Kepasone, an average score of greater than 95% was obtained, which means that the copolymer-1 sample and Kepasone have similar digested peptide composition . This can also be observed from the LC / MS data between these 11 runs ( Figure 1c ). When comparing 10 batches of Copaxone with one replicate of the negative control, there were several distinct peaks within the first 7 min ( Figure 1d ), where Copolymer-1 had negligible peaks in this region, indicating that certain digested peptides were only detected in Kepaso...
Embodiment 3
[0034] Similarity Evaluation by Hypothesis Testing
[0035] Statistical hypothesis testing is a method of statistical inference, usually applied in the comparison of 2 or more data sets. In the testing method, a statistical hypothesis is a testable hypothesis based on observations of a process modeled by a set of random variables. The inventors developed a hypothesis testing method to analyze high-dimensional LC-MS data to evaluate the degree of similarity between a reference drug and a generic. A feature of the hypothesis testing method proposed by the inventors is that all differences in data points between two sample groups are considered.
[0036] To first evaluate the feasibility of this method, 10 batches of Kepasson were randomly divided into two groups of 5 batches and their data points were used for the developed sum of squares test. Shows H for 0.0056 (p-value 0 was rejected, and different batches of Kepasone were significantly similar ( Figure 2a ). The invent...
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