Importance of Attention Preliminary Evidence of an Association Between an IL6 Promoter Polymorphism and Self-Reported Attentional Function in Oncology Patients and Their Family Caregivers John Merriman, MS, RN ICCTF Conference March 16, 2012 Navigating treatment options Maintaining healthy social relationships Accomplishing meaningful goals 2 Cimprich 2011 The Attention System Alerting network vigilance Orienting network selectivity Executive network effortful control attentional fatigue Posner 2012 communication to CNS release of communication CNS to CNS s 1
release of diminished i i d communication CNS attentional to CNS s function Purposes 1. Identify latent classes of oncology patients and family caregivers with distinct trajectories of attentional function 2. Determine relationships between participant characteristics, including gene polymorphisms, and latent class membership Design and Methods Descriptive, longitudinal study Participation criteria >18 years of age Able to read, write, and understand English Karnofsky Performance Status (KPS) score >60 Scheduled to receive primary/adjuvant RT or family caregiver No metastases No more than one cancer diagnosis No diagnosed sleep disorders Study Procedures Recruitment at the time of simulation Written informed consent Seven assessments over six months Baseline assessment at simulation The midpoint and endpoint of RT Once a month for an additional four months Attentional Function Index (AFI) 16-item inventory 0-to-10 NRS Total score is the mean of the items Low levels of attentional function <5.0 Moderate levels 5.0-7.5 High levels >7.5 Demonstrated validity and reliability Phenotypic Analyses Growth mixture modeling (GMM) New technique Latent class identification Better phenotyping Cimprich 2011 Muthen 2000 2
n=39 (16%) n=121 (48%) n=92 (37%) Demographic and Clinical Characteristics Age (years) 65 (9) 63 (10) 58 (13) 3 < 1,2 Education (years) 16 (3) 16 (3) 16 (3) n.s. Comorbidities* 4 (2) 5 (3) 5 (3) 3 > 1 KPS score* 96 (9) 94 (10) 88 (14) 3 < 1,2 Female 20 (51) 59 (49) 56 (61) n.s. White 32 (82) 94 (78) 61 (66) n.s. Married/partnered* 33 (85) 87 (73) 54 (59) 3 < 1 Genotypic Data Collection Genotyping GoldenGate genotyping platform Blinded to clinical status 104 SNPs across 15 candidate genes IFNG1, IFNGR1, IL1B, IL1R1, IL2, IL8, IL17A, NFKB1, NFKB2, TNFA, IL1R2, IL4, IL10, IL13, IL6 Haplotypes (SNP combinations) Determined if haplotypes improved strength of association with phenotype Patient* 19 (49) 78 (65) 70 (76) 3 > 1 Genetic Association Analyses Univariate analysis Logistic regression models Only KPS remained a significant phenotypic predictor Controlled for functional status and race/ethnicity If overall model included a significant genotype, pairwise post hoc contrasts of classes n=39 (16%) n=121 (48%) n=92 (37%) 3
Genotypic Differences Among Classes Gene SNP MAF Alleles P Model IL4 rs2243250 0.26 C>T.047 A IL4 rs2227284 0.40 C>A.013 A IL4 rs2227282 0.40 C>G.013 A IL4 rs2243274 0.26 G>A.020 A IL4 HapA1 - -.033 - IL6 rs2069827 0.07 G>T.002 D IL6 rs1800796 0.10 G>C.007 D IL6 rs1800795 0.36 C>G.010 A IL6 rs2066992 0.09 G>T.007 D IL6 HapA6 - -.005 - NFKB2 rs7897947 0.23 T>G.048 D Genotypic Differences Among Classes Gene SNP MAF Alleles P Model IL4 rs2243250 0.26 C>T.047 A IL4 rs2227284 0.40 C>A.013 A IL4 rs2227282 0.40 C>G.013 A IL4 rs2243274 0.26 G>A.020 A IL4 HapA1 - -.033 - IL6 rs2069827 0.07 G>T.002 D IL6 rs1800796 0.10 G>C.007 D IL6 rs1800795 0.36 C>G.010 A IL6 rs2066992 0.09 G>T.007 D IL6 HapA6 - -.005 - NFKB2 rs7897947 0.23 T>G.048 D hoc: High Versus Improving Classes IL6 genotype 3.98 1.64 1.77, 8.92.001 KPS 0.56 0.15 0.33, 0.95.031 Overall model fit: χ 2 = 25.07, p =.002, R 2 = 0.15 Poor outcomes for carriers of the G allele Associated with elevated levels of IL6 High levels associated with poor outcomes Associated with symptoms of sickness behavior, including difficulty concentrating Protein Data Bank; Spath-Schwalbe, 1998; DeMichele, 2009; Bull, 2009; Hulkkonen, 2001 Research Possibilities Sample size Other physiological pathways Patrick Swift William Wara Brad Aouizerat Kathy Lee Claudia West Imaging Objective tests Chris Miaskowski Marylin Dodd Bruce Cooper Steve Paul Laura Dunn Funding: National Institute of Nursing Research, American Cancer Society, Oncology Nursing Society Posner 2007 4
References 1. Cimprich B, Visovatti M, Ronis DL. The Attentional Function Index-a self-report cognitive measure. Psychooncology. Mar 9 2011. Posner M. Attention in a Social 2. World. New York: Oxford University Press, 2012. 3. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. Mar 2007;7(3):192-201. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology 4. meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1): 137-62. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on 5. health and cognition. Neurosci Biobehav Rev. Sep 2010;35(1):2-16. 6. Muthen, B. (2000). Integrating gperson-centered and variable-centered analyses: GMM with latent trajectory classes. Spath-Schwalbe E, 7. Hansen K, Schmidt F, et al. Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab. May 1998;83(5):1573-1579. DeMichele A, Gray R, Horn M, et al. Host genetic variants in the interleukin-6 promoter predict 8. poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. Cancer Res. May 15 2009;69(10):4184-4191. Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and 9. serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Molecular psychiatry. Dec 2009;14(12):1095-1104. 10. Hulkkonen J, Pertovaara M, Antonen J, Pasternack A, Hurme M. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjogren's syndrome and correlate with the clinical manifestations of the disease. Rheumatology (Oxford). Jun 2001;40(6):656-661. 11. Posner MI, Rothbart MK, Sheese BE. Attention genes. Dev Sci 2007;10(1): 24-9. Symptom Characteristics STAI-S 23.9 (5.8) 29.2 (9.6) 36.3 (11.5) 3>2>1 STAI-T 25.6 (5.6) 32.3 (9.0) 40.0 (8.9) 3>2>1 CES-D 3.8 (4.5) 6.7 (6.4) 13.8 (8.9) 3>2>1 GSDS 25.1 (11.1) 37.0 (16.7) 47.1 (19.6) 3>2>1 Evening fatigue 2.8 (2.0) 4.3 (2.0) 4.9 (1.8) 2,3>1 Morning fatigue 1.1 (1.8) 2.0 (1.8) 3.1 (1.8) 3>2>1 AFI score 9.1 (0.7) 7.7 (1.1) 5.7 (1.6) 3<2<1 Pain (% yes) 10 (26) 58 (48) 53 (58) 2,3>1 Symptom Characteristics Symptom Characteristics STAI-S 23.9 (5.8) 29.2 (9.6) 36.3 (11.5) 3>2>1 STAI-T 25.6 (5.6) 32.3 (9.0) 40.0 (8.9) 3>2>1 CES-D 3.8 (4.5) 6.7 (6.4) 13.8 (8.9) 3>2>1 GSDS 25.1 (11.1) 37.0 (16.7) 47.1 (19.6) 3>2>1 Evening fatigue 2.8 (2.0) 4.3 (2.0) 4.9 (1.8) 2,3>1 Morning fatigue 1.1 (1.8) 2.0 (1.8) 3.1 (1.8) 3>2>1 AFI score 9.1 (0.7) 7.7 (1.1) 5.7 (1.6) 3<2<1 Pain (% yes) 10 (26) 58 (48) 53 (58) 2,3>1 STAI-S 23.9 (5.8) 29.2 (9.6) 36.3 (11.5) 3>2>1 STAI-T 25.6 (5.6) 32.3 (9.0) 40.0 (8.9) 3>2>1 CES-D 3.8 (4.5) 6.7 (6.4) 13.8 (8.9) 3>2>1 GSDS 25.1 (11.1) 37.0 (16.7) 47.1 (19.6) 3>2>1 Evening fatigue 2.8 (2.0) 4.3 (2.0) 4.9 (1.8) 2,3>1 Morning fatigue 1.1 (1.8) 2.0 (1.8) 3.1 (1.8) 3>2>1 AFI score 9.1 (0.7) 7.7 (1.1) 5.7 (1.6) 3<2<1 Pain (% yes) 10 (26) 58 (48) 53 (58) 2,3>1 Demographic and Clinical Characteristics Age 65 (9) 63 (10) 58 (13) 3 < 1,2 Education 16 (3) 16 (3) 16 (3) - Comorbidities 4 (2) 5 (3) 5 (3) 3 > 1 KPS score 96 (9) 94 (10) 88 (14) 3 < 1,2 IL6 Haplotype A6 Gene SNP MAF Alleles P Model IL6 rs1800795 0.355 C>G.010 A IL6 rs2069835 0.066 T>C.474 A IL6 rs1554606 0.405 T>G.141 A IL6 rs2069845 0.405 G>A.141 A IL6 rs2069861 0.083 C>T.248 A IL6 rs35610689 0.242 A>G.755 A Female 20 (51) 59 (49) 56 (61) - White 32 (82) 94 (78) 61 (66) - Married/partnered 33 (85) 87 (73) 54 (59) 3 < 1 Patient 19 (49) 78 (65) 70 (76) 3 > 1 5
32 IL6 (rs1800 0795) - Percent 100 CC CG GG 80 60 40 20 n=18 n=20 n=39 n=53 n=23 n=46 n=33 n=9 GMM Fit Indices GMM LL AIC BIC Entropy VLMR c 1-class -2320.300 4668.600 4718.012 n/a n/a 2-class -2262.120 4568.241 4645.888 0.685 116.359* 3-class -2251.400 4556.800 4652.094 0.693 21.441* 4-class -2245.108 4554.217 4667.158 0.745 12.583 0 n=1 High AF Improving AF Moderate AF GMM Parameter Estimates (n=39, 15.5%) Mean (SE) (n=92, 36.5%) Intercept 9.0 (0.1)* 7.5 (0.2)* 5.5 (0.2)* Linear slope 0.2(0.073) 073)* 0.2(0.1) 1)* -0.2(0.1) Quadratic slope -0.01 (0.01) -0.02 (0.01)* 0.04 (0.02)* Overall Model IL6 genotype 2.64 0.91 1.34, 5.21 0.005 KPS 0.53 0.13 0.32, 0.86 0.010 Overall model fit: χ 2 = 24.28, p =.002, R 2 = 0.12 Variances Intercept fixed at 0 0.6 (0.1) 1.4 (0.3) Linear Slope fixed at 0 fixed at 0 0.05 (0.01) 6
hoc: High Versus Improving Classes With Age in the Model IL6 genotype 4.11 1.72 1.81, 9.34.001 KPS 0.57 0.16 0.34, 0.98.042 Age 0.89 0.11 0.70, 1.13.351 Overall model fit: χ 2 = 25.95, p =.002, R 2 = 0.15 hoc: High Versus Improving Classes With Race/Ethnicity Shown IL6 genotype 3.98 1.64 1.77, 8.92.001 KPS 0.56 0.15 0.33, 0.95.031 pc1_ev_87 770 7.70x10 13 214 2.14x1010 15 159 1.59x1010-10, 373 3.73x10 37.251 pc2_ev_66 6.28x10-7 1.61x10-5 9.39x10-29, 4.20x10 15.578 pc3_ev_30 4.35x10-21 7.63x10-20 5.21x10-36, 3.64x10-06.007 _Iethnicge~1 3.07 6.32.05, 174.18.587 _Iethnicge~2 0.19 0.35 0.01, 6.95.364 _Iethnicge~3 3.03 3.73 0.27, 33.86.368 Overall model fit: χ 2 = 25.07, p =.002, R 2 = 0.15 Schematic of IL6 Gene Miaskowski et al. current study Smith et al. Collado-Hidalgo et al. Smith, A. J. P. et al. Clin Chem 2008;54:841-850 Copyright 2008 American Association for Clinical Chemistry 7