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## ABOUT ## ABOUT
This program simulates BiGpairSEQ (Bipartite Graph pairSEQ), a graph theory-based adaptation This program simulates BiGpairSEQ (Bipartite Graph pairSEQ), a graph theory-based adaptation
of the pairSEQ algorithm (Howie et al. 2015) for pairing T cell receptor sequences. of the pairSEQ algorithm (Howie, et al. 2015) for pairing T cell receptor sequences.
## THEORY ## THEORY
@@ -20,14 +20,13 @@ The problem of pairing TCRA/TCRB sequences thus reduces to the "assignment probl
matching on a bipartite graph--the subset of vertex-disjoint edges whose weights sum to the maximum possible value. matching on a bipartite graph--the subset of vertex-disjoint edges whose weights sum to the maximum possible value.
This is a well-studied combinatorial optimization problem, with many known solutions. This is a well-studied combinatorial optimization problem, with many known solutions.
The best currently-known algorithm for bipartite graphs with integer weights--which is what BiGpairSEQ uses-- The best currently-known algorithm for bipartite graphs with integer weights--which is what BiGpairSEQ uses--is
is from Duan and Su (2012). For a graph with m edges, n vertices per side, and maximum integer edge weight N, from Duan and Su (2012). For a graph with m edges, n vertices per side, and maximum integer edge weight N,
their algorithm runs in **O(m sqrt(n) log(N))** time. This is the best known efficiency for finding a maximum weight their algorithm runs in **O(m sqrt(n) log(N))** time. This is the best known efficiency for finding a maximum weight
matching on a bipartite graph, and the integer edge weight requirement makes it ideal for BiGpairSEQ. matching on a bipartite graph, and the integer edge weight requirement makes it ideal for BiGpairSEQ.
Unfortunately, it's a fairly new algorithm, and the integer edge weight requirement makes it less generically useful. Unfortunately, it's a fairly new algorithm. It is not implemented by the graph theory library used in this simulator.
It is not implemented by the graph theory library used in this simulator. So this program So this program instead uses the Fibonacci heap-based algorithm of Fredman and Tarjan (1987), which has a worst-case
instead uses the Fibonacci heap-based algorithm of Fredman and Tarjan (1987), which has a worst-case
runtime of **O(n (n log(n) + m))**. The algorithm is implemented as described in Melhorn and Näher (1999). runtime of **O(n (n log(n) + m))**. The algorithm is implemented as described in Melhorn and Näher (1999).
The current version of the program uses a pairing heap instead of a Fibonacci heap for its priority queue, The current version of the program uses a pairing heap instead of a Fibonacci heap for its priority queue,
@@ -81,9 +80,9 @@ writing files, the program will automatically add the correct extension to any f
#### Cell Sample Files #### Cell Sample Files
Cell Sample files consist of any number of distinct "T cells." Every cell contains Cell Sample files consist of any number of distinct "T cells." Every cell contains
four sequences: Alpha CDR3, Beta CDR, Alpha CDR1, Beta CDR1. The sequences are represented by four sequences: Alpha CDR3, Beta CDR3, Alpha CDR1, Beta CDR1. The sequences are represented by
random integers. CDR3 Alpha and Beta sequences are all unique. CDR1 Alpha and Beta sequences random integers. CDR3 Alpha and Beta sequences are all unique within a given Cell Sample file. CDR1 Alpha and Beta sequences
are not necessarily unique; the relative diversity can be set when making a Cell Sample file. are not necessarily unique; the relative diversity can be set when making the file.
(Note: though cells still have CDR1 sequences, matching of CDR1s is currently awaiting re-implementation.) (Note: though cells still have CDR1 sequences, matching of CDR1s is currently awaiting re-implementation.)
@@ -108,9 +107,9 @@ Structure:
Sample Plate files consist of any number of "wells" containing any number of T cells (as Sample Plate files consist of any number of "wells" containing any number of T cells (as
described above). The wells are filled randomly from a Cell Sample file, according to a selected described above). The wells are filled randomly from a Cell Sample file, according to a selected
frequency distribution. Additionally, every individual sequence within each cell may, with some frequency distribution. Additionally, every individual sequence within each cell may, with some
given dropout probability, be omitted from the file. This simulates the effect of amplification errors given dropout probability, be omitted from the file; this simulates the effect of amplification errors
prior to sequencing. Plates can also be partitioned into any number of (approximately) evenly-sized prior to sequencing. Plates can also be partitioned into any number of sections, each of which can have a
sections, each of which can have a different number of T cells per well. different concentration of T cells per well.
Options when making a Sample Plate file: Options when making a Sample Plate file:
* Cell Sample file to use * Cell Sample file to use
@@ -120,7 +119,7 @@ Options when making a Sample Plate file:
* Standard deviation size * Standard deviation size
* Exponential * Exponential
* Lambda value * Lambda value
* Based on the slope of the graph in Figure 4C of the pairSEQ paper, the distribution of the original experiment was exponential with a lambda of approximately 0.6. (Howie et al. 2015) * (Based on the slope of the graph in Figure 4C of the pairSEQ paper, the distribution of the original experiment was exponential with a lambda of approximately 0.6. (Howie, et al. 2015))
* Total number of wells on the plate * Total number of wells on the plate
* Number of sections on plate * Number of sections on plate
* Number of T cells per well * Number of T cells per well
@@ -128,13 +127,13 @@ Options when making a Sample Plate file:
* Dropout rate * Dropout rate
Files are in CSV format. There are no header labels. Every row represents a well. Files are in CSV format. There are no header labels. Every row represents a well.
Every column represents an individual cell, containing four sequences, represented by an array string: Every column represents an individual cell, containing four sequences, depicted as an array string:
`[CDR3A, CDR3B, CDR1A, CDR1B]`. So a representative cell might look like this: `[CDR3A, CDR3B, CDR1A, CDR1B]`. So a representative cell might look like this:
`[525902, 791533, -1, 866282]` `[525902, 791533, -1, 866282]`
Notice that the Alpha CDR1 is missing in the cell above, due to sequence dropout. Notice that the CDR1 Alpha is missing in the cell above--sequence dropout from simulated amplification error.
Dropouts are represented by replacing sequences with the value `-1`. Comments are preceded by `#` Dropout sequences are replaced with the value `-1`. Comments are preceded by `#`
Structure: Structure:
@@ -144,26 +143,26 @@ Structure:
# Each row represents one well on the plate # Each row represents one well on the plate
# Plate size: # Plate size:
# Concentrations: # Concentrations:
# Lambda: # Lambda -or- StdDev:
``` ```
| Well 1, cell 1 | Well 1, cell 2 | Well 1, cell 3| ... | | Well 1, cell 1 | Well 1, cell 2 | Well 1, cell 3| ... |
|---|---|---|---| |---|---|---|---|
| **Well 2, cell 1** | **Well 2, cell 2** | **Well 2, cell 3**| ... | | **Well 2, cell 1** | **Well 2, cell 2** | **Well 2, cell 3**| **...** |
| **Well 3, cell 1** | **Well 3, cell 2** | **Well 3, cell 3**| ... | | **Well 3, cell 1** | **Well 3, cell 2** | **Well 3, cell 3**| **...** |
| ... | ... | ... | ... | | **...** | **...** | **...** | **...** |
--- ---
#### Graph and Data Files #### Graph and Data Files
Graph and Data files are serialized binaries of a Java object containing the graph representation of a Graph and Data files are serialized binaries of a Java object containing the weigthed bipartite graph representation of a
Sample Plate and necessary metadata for matching and results output. Making them requires a Cell Sample file (to construct a list of correct sequence pairs for checking Sample Plate, along with the necessary metadata for matching and results output. Making them requires a Cell Sample file
the accuracy of BiGpairSEQ simulations) and a Sample Plate file (to construct the associated (to construct a list of correct sequence pairs for checking the accuracy of BiGpairSEQ simulations) and a
occupancy graph). These files can be several gigabytes in size. Writing them to a file lets us generate a graph and Sample Plate file (to construct the associated occupancy graph). These files can be several gigabytes in size.
its metadata once, then use it for multiple different BiGpairSEQ simulations. Writing them to a file lets us generate a graph and its metadata once, then use it for multiple different BiGpairSEQ simulations.
Options for creating a Graph and Data file: Options for creating a Graph and Data file:
* The Cell Sample file to use * The Cell Sample file to use
* The Sample Plate file (generated from the given Cell Sample file) to use. * The Sample Plate file to use. (This must have been generated from the selected Cell Sample file.)
These files do not have a human-readable structure, and are not portable to other programs. (Export of graphs in a These files do not have a human-readable structure, and are not portable to other programs. (Export of graphs in a
portable data format may be implemented in the future. The tricky part is encoding the necessary metadata.) portable data format may be implemented in the future. The tricky part is encoding the necessary metadata.)
@@ -181,10 +180,9 @@ Options when running a BiGpairSEQ simulation of CDR3 alpha/beta matching:
* The maximum number of alpha/beta overlap wells to attempt to match * The maximum number of alpha/beta overlap wells to attempt to match
* (must be <= the number of wells on the plate - 1) * (must be <= the number of wells on the plate - 1)
* The maximum difference in alpha/beta occupancy to attempt to match * The maximum difference in alpha/beta occupancy to attempt to match
* (To skip using this filter, enter a value >= the number of wells on the plate) * (Optional. To skip using this filter, enter a value >= the number of wells on the plate)
* The minimum percentage of a sequence's occupied wells shared by another sequence to attempt to match * The minimum overlap percentage--the percentage of a sequence's occupied wells shared by another sequence--to attempt to match. Given as value in range 0 - 100.
* given value from 0 to 100 * (Optional. To skip using this filter, enter 0)
* (To skip using this filter, enter 0)
Example output: Example output:
@@ -223,24 +221,26 @@ using the (2021 corrected) formula from the original pairSEQ paper. (Howie, et a
## TODO ## TODO
* ~~Try invoking GC at end of workloads to reduce paging to disk~~ DONE * ~~Try invoking GC at end of workloads to reduce paging to disk~~ DONE
* ~~Hold graph data in memory until another graph is read-in?~~ * ~~Hold graph data in memory until another graph is read-in?~~ ABANDONED
* No, this won't work, because BiGpairSEQ simulations alter the underlying graph based on filtering constraints. Changes would cascade with multiple experiments. * *No, this won't work, because BiGpairSEQ simulations alter the underlying graph based on filtering constraints. Changes would cascade with multiple experiments.*
* See if there's a reasonable way to reformat Sample Plate files so that wells are columns instead of rows.
* ~~Problem is variable number of cells in a well~~
* ~~Apache Commons CSV library writes entries a row at a time~~
* _Got this working, but at the cost of a profoundly strange bug in graph occupancy filtering. Have reverted the repo until I can figure out what caused that. Given how easily Thingiverse transposes CSV matrices in R, might not even be worth fixing._
* Re-implement command line arguments, to enable scripting and statistical simulation studies
* Implement sample plates with random numbers of T cells per well.
* Possible BiGpairSEQ advantage over pairSEQ: BiGpairSEQ is resilient to variations in well populations; pairSEQ is not.
* preliminary data suggests that BiGpairSEQ behaves roughly as though the whole plate had whatever the *average* well concentration is, but that's still speculative.
* Enable GraphML output in addition to serialized object binaries, for data portability * Enable GraphML output in addition to serialized object binaries, for data portability
* Custom vertex type with attribute for sequence occupancy? * Custom vertex type with attribute for sequence occupancy?
* Re-implement CDR1 matching method * Re-implement CDR1 matching method
* Re-implement command line arguments, to enable scripting and statistical simulation studies * Implement Duan and Su's maximum weight matching algorithm
* Implement Duan and Su's maximum weight matching algorithms
* Add controllable algorithm-type parameter? * Add controllable algorithm-type parameter?
* Test whether pairing heap (currently used) or Fibonacci heap is more efficient for current matching algorithm * Test whether pairing heap (currently used) or Fibonacci heap is more efficient for priority queue in current matching algorithm
* in theory Fibonacci heap should be more efficient, but complexity overhead may eliminate theoretical advantage * in theory Fibonacci heap should be more efficient, but complexity overhead may eliminate theoretical advantage
* Add controllable heap-type parameter? * Add controllable heap-type parameter?
* Implement sample plates with random numbers of T cells per well
* Possible BiGpairSEQ advantage over pairSEQ: BiGpairSEQ is resilient to variations in well populations; pairSEQ is not.
* preliminary data suggests that BiGpairSEQ behaves roughly as though the whole plate had whatever the *average* well concentration is, but that's still speculative.
* See if there's a reasonable way to reformat Sample Plate files so that wells are columns instead of rows
* Problem is variable number of cells in a well
* Apache Commons CSV library writes entries a row at a time
* Can possibly sort the wells by length first, then construct entries
## CITATIONS ## CITATIONS
* Howie, B., Sherwood, A. M., et al. ["High-throughput pairing of T cell receptor alpha and beta sequences."](https://pubmed.ncbi.nlm.nih.gov/26290413/) Sci. Transl. Med. 7, 301ra131 (2015) * Howie, B., Sherwood, A. M., et al. ["High-throughput pairing of T cell receptor alpha and beta sequences."](https://pubmed.ncbi.nlm.nih.gov/26290413/) Sci. Transl. Med. 7, 301ra131 (2015)
@@ -259,4 +259,4 @@ BiGpairSEQ was conceived in collaboration with Dr. Alice MacQueen, who brought t
pairSEQ paper to the author's attention and explained all the biology terms he didn't know. pairSEQ paper to the author's attention and explained all the biology terms he didn't know.
## AUTHOR ## AUTHOR
Eugene Fischer, 2021. UI improvements and documentation, 2022. BiGpairSEQ algorithm and simulation by Eugene Fischer, 2021. UI improvements and documentation, 2022.