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Re evaluating the Categorization of HIV Progression in Subjects Based on CD4 T cell Decline
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Re evaluating the Categorization of HIV Progression in Subjects Based on CD4 T cell Decline
Rates
Angela Garibaldi & Ryan WillhiteLoyola Marymount University
BIOL 398-01/S10
March 2, 2010
Angela Garibaldi & Ryan WillhiteLoyola Marymount University
BIOL 398-01/S10
March 2, 2010
Outline Outline Review of the Markham method of labeling compared
with CD4 T cell decline rate categorization of progressors.
Selection Process Prediction Statistical Approach Results Discussion/ Comparison to More Recent Studies References
Review of the Markham method of labeling compared with CD4 T cell decline rate categorization of progressors.
Selection Process Prediction Statistical Approach Results Discussion/ Comparison to More Recent Studies References
Categorizing Progressors by CD4 T cell Count
Categorizing Progressors by CD4 T cell Count
Patterns of HIV-1 evolution in individuals with differing rates if CD4 T cell decline Rapid Progressors
Fewer than 200 CD4 T cells, within 2 years of seroconversion
Moderate Progressors CD4 T cell levels 200-650 during 4 year period
Non-progressors CD4 T cell levels above 650
Patterns of HIV-1 evolution in individuals with differing rates if CD4 T cell decline Rapid Progressors
Fewer than 200 CD4 T cells, within 2 years of seroconversion
Moderate Progressors CD4 T cell levels 200-650 during 4 year period
Non-progressors CD4 T cell levels above 650
Selecting Subjects to AnalyzeSelecting Subjects to Analyze
Selecting Subject ClonesSelecting Subject Clones
Selected the most recent visits that had sequenced clones. (Many had 0 clones for last 3+ visits)
Utilized only “Distinct Sequences”
Selected the most recent visits that had sequenced clones. (Many had 0 clones for last 3+ visits)
Utilized only “Distinct Sequences”
What we predict…What we predict… Subj. 6 (Moderate Test) and 13 (Non-Progressor)
will be less divergent and have less diversity than when 6 is compared to another Moderate (5,7)
Subj. 7 (Moderate Test) and 10 (Rapid-Progressor) will be less divergent and have less diversity than when 7 is compared to another Moderate (5,6)
Subj. 6 and 7 will be more divergent and have higher diversity in comparison to values generated in the above.
Subj. 6 (Moderate Test) and 13 (Non-Progressor) will be less divergent and have less diversity than when 6 is compared to another Moderate (5,7)
Subj. 7 (Moderate Test) and 10 (Rapid-Progressor) will be less divergent and have less diversity than when 7 is compared to another Moderate (5,6)
Subj. 6 and 7 will be more divergent and have higher diversity in comparison to values generated in the above.
Statistical ApproachStatistical Approach Utilized BedRock Conduct Clustdist multiple sequence
alignment for comparison and frequency values used to :
Calculate ''S'' ''Theta” to measure Divergence ''Minimum'' and ''Maximum” S/Number of clones to interpret Diversity
Utilized BedRock Conduct Clustdist multiple sequence
alignment for comparison and frequency values used to :
Calculate ''S'' ''Theta” to measure Divergence ''Minimum'' and ''Maximum” S/Number of clones to interpret Diversity
ResultsResults
Subject Number of Clones
S Theta Min difference
Max difference
Range
6 vs 13 53 93 20.48 38 50 127 vs 10 62 96 20.43 27 42 156 vs 7 53 93 20.48 26 41 156 vs 5 49 90 20.18 23 42 197 vs 5 48 83 18.69 34 49 1510 vs 5 59 103 22.15 30 48 1213 vs 5 43 79 18.22 34 46 12
DivergenceDivergence Min. and Max. values show that 6 and 10 are most
divergent Considers Frequencies
Min. and Max. values show that 6 and 10 are most divergent
Considers Frequencies
Divergence using Theta ValuesDivergence using Theta Values
Diversity shows a clearer pictureDiversity shows a clearer picture
Diversity similarities between (6,5) & (13,5) Diversity similarities between (6,5) & (13,5)
Revisiting the ResultsRevisiting the Results
Divergence does not prove to be an accurate method of categorizing
Theta did not deliver insight Diversity levels are similar in certain
categories
Divergence does not prove to be an accurate method of categorizing
Theta did not deliver insight Diversity levels are similar in certain
categories
Implications of using CD4 Tcell Decline Rate to Categorize
Implications of using CD4 Tcell Decline Rate to Categorize
This method is Better than Markham’s method of categorization
Especially in categorizing moderates from rapids Not as successful
without a larger sample size Not much success in comparing all
In the future Find a way to calculate the significance A larger sample size Use a program that would allow a comparison with higher number of
clones Few clones available from subjects may complicate the reliability. Focus on most recent visits and acquire clones for these visits
This method is Better than Markham’s method of categorization
Especially in categorizing moderates from rapids Not as successful
without a larger sample size Not much success in comparing all
In the future Find a way to calculate the significance A larger sample size Use a program that would allow a comparison with higher number of
clones Few clones available from subjects may complicate the reliability. Focus on most recent visits and acquire clones for these visits
More Recent StudyMore Recent Study
Nucleotide and amino acid mutations in human immunodeficiency virus corresponding to
CD4+ decline
M. D. Hill and W. Hern´andez
Ponce School of Medicine, Ponce, Puerto Rico
Published online January 3, 2006 _c Springer-Verlag 2006
Nucleotide and amino acid mutations in human immunodeficiency virus corresponding to
CD4+ decline
M. D. Hill and W. Hern´andez
Ponce School of Medicine, Ponce, Puerto Rico
Published online January 3, 2006 _c Springer-Verlag 2006
Comparing our findings to more recent studies
Comparing our findings to more recent studies
Change in diversity of nucleotide sequences among HIV forms within individuals as their CD4+ counts progressed
There is a trend for the average distance to increase with dropping CD4+ values
Among all progressors, 94.1% of subjects demonstrated increased diversity
The rapid progressors had a statistically significant higher loop charge
Four of the rapid progressors had T-tropism
Change in diversity of nucleotide sequences among HIV forms within individuals as their CD4+ counts progressed
There is a trend for the average distance to increase with dropping CD4+ values
Among all progressors, 94.1% of subjects demonstrated increased diversity
The rapid progressors had a statistically significant higher loop charge
Four of the rapid progressors had T-tropism
How Does this Compare?…How Does this Compare?… Found that progression is easier to evaluate than
non-progression in terms of diversity The moderate and rapid progressor were most
divergent Therefore there is an accumulation of differences
over a period of time
Perhaps there needs to be further investigation in: RNA and DNA sequences A closer look at regions described in paper such as
loop charge
Found that progression is easier to evaluate than non-progression in terms of diversity
The moderate and rapid progressor were most divergent Therefore there is an accumulation of differences
over a period of time
Perhaps there needs to be further investigation in: RNA and DNA sequences A closer look at regions described in paper such as
loop charge
ReferencesReferences
Markham RB, Wang WC, Weisstein AE, Wang Z, Munoz A, Templeton A, Margolick J, Vlahov D, Quinn T, Farzadegan H, and Yu XF. Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline. Proc Natl Acad Sci U S A 1998 Oct 13; 95(21) 12568-73. pmid:9770526.
Hill MD and Hern ndez W. � Nucleotide and amino acid mutations in human immunodeficiency virus corresponding to CD4+ decline. Arch Virol 2006 Jun; 151(6) 1149-58. doi:10.1007/s00705-005-0693-8 pmid:16385396. PubMed HubMed PubGet [Paper1]
HIV project handout for statistical analysis info
Markham RB, Wang WC, Weisstein AE, Wang Z, Munoz A, Templeton A, Margolick J, Vlahov D, Quinn T, Farzadegan H, and Yu XF. Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline. Proc Natl Acad Sci U S A 1998 Oct 13; 95(21) 12568-73. pmid:9770526.
Hill MD and Hern ndez W. � Nucleotide and amino acid mutations in human immunodeficiency virus corresponding to CD4+ decline. Arch Virol 2006 Jun; 151(6) 1149-58. doi:10.1007/s00705-005-0693-8 pmid:16385396. PubMed HubMed PubGet [Paper1]
HIV project handout for statistical analysis info