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Section III: Detailed Analysis

Hierarchical cluster analysis of diagnostic cases using all genes that passed the variation filter
Two-dimensional hierarchical clustering was performed using Pearson correlation coefficient and an unweighted pair group method using arithmetic averages (GeneMaths, version 1.5). The results of hierarchical clustering of the 327 diagnostic samples using genes selected by a variety of metrics are shown below.

Methods for gene selection
Discriminating genes for the various leukemia subtypes were selected using a variety of statistical metrics. The individual metrics used and the list of selected probe sets and corresponding genes are given below. Genes selected by Chi-square, T-statistics, Wilkins', and CFS, were chosen using the decision tree format shown in Figure 19 below. In this process, genes were selected that distinguished the class for all classes listed below it in the decision tree structure. For the selection of genes using SOM/DAV genes were selected that distinguished the class from all others. The degree of overlap between the lists of genes selected for each genetic subtype by the various metrics is discussed below.

Chi-square
The Chi-square method evaluates each gene individually by measuring the Chi-square statistics with respect to the classes. The method first discretizes the observed expression values of the gene into several intervals using an entropy-based discretization method. The Chi-square statistics of a gene is then calculated as X² = ΣΣ(A_ij - E_ij)²/E_ij, summing over intervals i = 1..m and classes j = 1..k. A_ij is the number of samples in the i^thinterval that are of the j^th class. E_ij is the expected frequency of A_ij and is calculated as E_ij = R_i * C_i/N, where R_i is the number of samples in the i^th interval, C_j is the number of samples in the j^th class, and N is the total number of samples. The genes are then sorted according to their Chi-square statistics---the larger the Chi-square statistics, the more important the gene. The 40 genes with the highest Chi-square statistics in each subtype are listed in Table 11. Generally, using anywhere from the top 20 to 40 genes did not result in significant differences in subtype prediction accuracy. Therefore, we used only the top 20 genes in subtype prediction, unless noted otherwise.

Table 11. Genes selected by Chi-square


	Affymetrix number	Gene Name	GeneSymbol	Reference number	Chi- square value	Above/ Below Mean

*BCR-ABL*
1	1637_at	mitogen-activated protein kinase-activated protein kinase 3	MAPKAPK3	U09578	62.75	Above
2	36650_at	cyclin D2	CCND2	D13639	59.79	Above
3	40196_at	HYA22 protein	HYA22	D88153	54.79	Above
4	1635_at	proto-oncogene tyrosine-protein kinase ABL gene	ABL	U07563	54.77	Above
5	33775_s_at	caspase 8 apoptosis-related cysteine protease	CASP8	X98176	49.70	Above
6	1636_g_at	proto-oncogene tyrosine-protein kinase ABL gene	ABL	U07563	48.29	Above
7	41295_at	GTT1 protein	GTT1	AL041780	42.60	Above
8	37600_at	extracellular matrix protein 1	ECM1	U68186	42.60	Above
9	37012_at	capping protein actin filament muscle Z-line beta	CAPZB	U03271	38.46	Above
10	39225_at	alkylglycerone phosphate synthase	AGPS	Y09443	38.46	Above
11	1326_at	caspase 10 apoptosis-related cysteine protease	CASP10	U60519	37.83	Above
12	34362_at	solute carrier family 2 facilitated glucose transporter member 5	SLC2A5	M55531	37.54	Above
13	33150_at	disrupter of silencing 10	SAS10	AI126004	36.95	Above
14	40051_at	TRAM-like protein	KIAA0057	D31762	36.95	Above
15	39061_at	bone marrow stromal cell antigen 2	BST2	D28137	36.95	Above
16	33172_at	hypothetical protein FLJ10849	FLJ10849	T75292	36.95	Above
17	37399_at	aldo-keto reductase family 1 member C3 3-alpha hydroxysteroid dehydrogenase type II	AKR1C3	D17793	36.95	Above
18	317_at	protease cysteine 1 legumain	PRSC1	D55696	36.95	Above
19	40953_at	calponin 3 acidic	CNN3	S80562	33.94	Above
20	330_s_at	tubulin, alpha 1, isoform 44	TUBA1	HG2259-HT2348	33.32	Above
21	40504_at	paraoxonase 2	PON2	AF001601	31.46	Above
22	38578_at	tumor necrosis factor receptor superfamily member 7	TNFRSF7	M63928	30.47	Above
23	39044_s_at	diacylglycerol kinase delta 130kD	DGKD	D73409	29.59	Below
24	36634_at	BTG family member 2	BTG2	U72649	29.16	Below
25	38119_at	glycophorin C Gerbich blood group	GYPC	X12496	29.16	Above
26	32562_at	endoglin Osler-Rendu-Weber syndrome 1	ENG	X72012	27.96	Above
27	33228_g_at	interleukin 10 receptor beta	IL10RB	AI984234	27.70	Below
28	37006_at	step II splicing factor SLU7	SLU7	AI660656	27.15	Above
29	38641_at	Homo sapiens mRNA for TSC-22-like protein		AJ133115	27.15	Above
30	38220_at	dihydropyrimidine dehydrogenase	DPYD	U20938	27.15	Above
31	1211_s_at	CASP2 and RIPK1 domain containing adaptor with death domain	CRADD	U84388	26.46	Above
32	39730_at	v-abl Abelson murine leukemia viral oncogene homolog 1	ABL1	X16416	25.90	Above
33	36591_at	tubulin alpha 1 testis specific	TUBA1	X06956	25.90	Above
34	36035_at	anchor attachment protein 1 Gaa1p yeast homolog	GPAA1	AB002135	25.34	Above
35	980_at	Niemann-Pick disease type C1	NPC1	AF002020	25.29	Above
36	671_at	secreted protein acidic cysteine-rich osteonectin	SPARC	J03040	25.29	Above
37	40698_at	C-type calcium dependent carbohydrate-recognition domain lectin superfamily member 2 activation-induced	CLECSF2	X96719	23.80	Above
38	39330_s_at	actinin alpha 1	ACTN1	M95178	23.70	Above
39	1983_at	cyclin D2	CCND2	X68452	23.70	Above
40	2001_g_at	ataxia telangiectasia mutated	ATM	U26455	22.60	Above

*E2A-PBX1*
1	41146_at	ADP-ribosyltransferase NAD poly ADP-ribose polymerase	ADPRT	J03473	187.00	Above
2	1287_at	ADP-ribosyltransferase NAD poly ADP-ribose polymerase	ADPRT	J03473	187.00	Above
3	32063_at	pre-B-cell leukemia transcription factor 1	PBX1	M86546	187.00	Above
4	33355_at	Homo sapiens cDNA FLJ12900 fis clone NT2RP2004321 (by CELERA serach of target sequence = PBX1)	PBX1	AL049381	187.00	Above
5	430_at	nucleoside phosphorylase	NP	X00737	187.00	Above
6	40454_at	FAT tumor suppressor Drosophila homolog	FAT	X87241	176.11	Above
7	753_at	nidogen 2	NID2	D86425	164.28	Above
8	33821_at	Human DNA sequence from clone RP3-483K16 on chromosome 6p12.1-21.1	HELO1	AL034374	155.00	Above
9	39614_at	KIAA0802 protein	KIAA0802	AB018345	153.46	Above
10	38340_at	huntingtin interacting protein-1-related	KIAA0655	AB014555	143.85	Above
11	1786_at	c-mer proto-oncogene tyrosine kinase	MERTK	U08023	142.34	Above
12	39929_at	KIAA0922 protein	KIAA0922	AB023139	139.97	Above
13	39379_at	Homo sapiens mRNA cDNA DKFZp586C1019 from clone DKFZp586C1019		AL049397	139.49	Above
14	717_at	GS3955 protein	GS3955	D87119	135.24	Above
15	362_at	protein kinase C zeta	PRKCZ	Z15108	131.36	Above
16	33513_at	signaling lymphocytic activation molecule	SLAM	U33017	131.36	Above
17	37225_at	KIAA0172 protein	KIAA0172	D79994	131.36	Above
18	854_at	B lymphoid tyrosine kinase	BLK	S76617	130.95	Above
19	35974_at	lymphoid-restricted membrane protein	LRMP	U10485	123.33	Above
20	36452_at	synaptopodin	KIAA1029	AB028952	123.33	Above
21	40648_at	c-mer proto-oncogene tyrosine kinase	MERTK	U08023	120.51	Above
22	38393_at	KIAA0247 gene product	KIAA0247	D87434	120.51	Above
23	38994_at	STAT induced STAT inhibitor-2	STATI2	AF037989	118.58	Below
24	34861_at	golgi autoantigen golgin subfamily a 3	GOLGA3	D63997	116.80	Above
25	38748_at	adenosine deaminase RNA-specific B1 homolog of rat RED1	ADARB1	U76421	114.13	Above
26	40113_at	GS3955 protein	GS3955	D87119	114.13	Above
27	36179_at	mitogen-activated protein kinase-activated protein kinase 2	MAPKAPK2	U12779	113.43	Above
28	37493_at	colony stimulating factor 2 receptor beta low-affinity granulocyte-macrophage	CSF2RB	H04668	113.04	Above
29	578_at	Human recombination acitivating protein (RAG2) gene	RAG2	M94633	111.32	Above
30	41017_at	myosin-binding protein H	MYBPH	U27266	109.73	Above
31	37625_at	interferon regulatory factor 4	IRF4	U52682	108.51	Above
32	38679_g_at	small nuclear ribonucleoprotein polypeptide E	SNRPE	AA733050	106.02	Above
33	1389_at	membrane metallo-endopeptidase neutral endopeptidase enkephalinase CALLA CD10	MME	J03779	105.65	Below
34	34783_s_at	BUB3 budding uninhibited by benzimidazoles 3 yeast homolog	BUB3	AF047473	103.87	Above
35	36959_at	ubiquitin-conjugating enzyme E2 variant1	UBE2V1	U49278	103.87	Above
36	39864_at	cold inducible RNA-binding protein	CIRBP	D78134	99.76	Below
37	41862_at	KIAA0056 protein	KIAA0056	D29954	99.76	Above
38	41425_at	Friend leukemia virus integration 1	FLI1	M98833	96.47	Above
39	37177_at	CD58 antigen lymphocyte function-associated antigen 3	CD58	Y00636	93.84	Above
40	37485_at	fatty-acid-Coenzyme A ligase very long-chain 1	FACVL1	D88308	93.17	Above

Hyperdiploid >50
1	36620_at	superoxide dismutase 1 soluble amyotrophic lateral sclerosis 1 adult	SOD1	X02317	52.43	Above
2	37350_at	Human DNA sequence from clone 889N15 on chromosome Xq22.1-22.3.	PSMD10	AL031177	48.71	Above
3	171_at	von Hippel-Lindau binding protein 1	VBP1	U56833	45.80	Above
4	37677_at	phosphoglycerate kinase 1	PGK1	V00572	45.80	Above
5	41724_at	accessory proteins BAP31/BAP29	DXS1357E	X81109	45.58	Above
6	32207_at	membrane protein palmitoylated 1 55kD	MPP1	M64925	44.07	Above
7	38738_at	SMT3 suppressor of mif two 3 yeast homolog 1	SMT3H1	X99584	43.57	Above
8	40480_s_at	FYN oncogene related to SRC FGR YES	FYN	M14333	43.57	Above
9	38518_at	sex comb on midleg Drosophila like 2	SCML2	Y18004	43.20	Above
10	41132_r_at	heterogeneous nuclear ribonucleoprotein H2 H	HNRPH2	U01923	43.15	Above
11	31492_at	muscle specific gene	M9	AB019392	43.01	Below
12	38317_at	transcription elongation factor A SII like 1	TCEAL1	M99701	41.10	Above
13	40998_at	trinucleotide repeat containing 11 THR-associated protein 230 kDa subunit	TNRC11	AF071309	40.88	Above
14	35688_g_at	mature T-cell proliferation 1	MTCP1	Z24459	40.52	Above
15	40903_at	ATPase H transporting lysosomal vacuolar proton pump membrane sector associated protein M8-9	APT6M8-9	AL049929	40.33	Above
16	36489_at	phosphoribosyl pyrophosphate synthetase 1	PRPS1	D00860	40.33	Above
17	1520_s_at	interleukin 1 beta	IL1B	X04500	40.29	Above
18	35939_s_at	POU domain class 4 transcription factor 1	POU4F1	L20433	38.74	Above
19	38604_at	neuropeptide Y	NPY	AI198311	38.26	Above
20	31863_at	KIAA0179 protein	KIAA0179	D80001	38.26	Above
21	890_at	ubiquitin-conjugating enzyme E2A RAD6 homolog	UBE2A	M74524	37.99	Above
22	39402_at	interleukin 1 beta	IL1B	M15330	37.92	Above
23	41490_at	phosphoribosyl pyrophosphate synthetase 2	PRPS2	Y00971	37.72	Above
24	34753_at	synaptobrevin-like 1	SYBL1	X92396	37.72	Above
25	40891_f_at	DNA segment on chromosome X unique 9879 expressed sequence	DXS9879E	X92896	37.15	Above
26	306_s_at	high-mobility group nonhistone chromosomal protein 14	HMG14	J02621	37.15	Above
27	37640_at	hypoxanthine phosphoribosyltransferase 1 Lesch-Nyhan syndrome	HPRT1	M31642	37.15	Above
28	34829_at	dyskeratosis congenita 1 dyskerin	DKC1	U59151	36.48	Above
29	36169_at	NADH dehydrogenase ubiquinone 1 alpha subcomplex 1 7.5kD MWFE	NDUFA1	N47307	36.48	Above
30	38968_at	SH3-domain binding protein 5 BTK-associated	SH3BP5	AB005047	35.95	Above
31	36128_at	transmembrane trafficking protein	TMP21	L40397	35.88	Above
32	37014_at	myxovirus influenza resistance 1 homolog of murine interfer