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To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers
Open accessAbstract
Behavioral scientists have increasingly included inflammatory biology as mechanisms in their investigation of psychosocial dynamics on the pathobiology of disease. However, a lack of standardization of inclusion and exclusion criteria and assessment of relevant control variables impacts the interpretation of these studies. The present paper reviews and discusses human biobehavioral factors that can affect the measurement of circulating markers of inflammation. Keywords relevant to inflammatory biology and biobehavioral factors were searched through PubMed. Age, sex, and hormonal status, socioeconomic status, ethnicity and race, body mass index, exercise, diet, caffeine, smoking, alcohol, sleep disruption, antidepressants, aspirin, and medications for cardiovascular disease are all reviewed. A tiered set of recommendations as to whether each variable should be assessed, controlled for, or used as an exclusion criteria is provided. These recommendations provide a framework for observational and intervention studies investigating linkages between psychosocial and behavioral factors and inflammation.
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“Health behaviors were assessed using validated self-report items (O’Connor et al., 2009) including cigarette smoking status (never/former/current), alcohol use (drinks per week), and physical activity (minutes per week of moderate-to-vigorous intensity activity).”
From Strong Enough to Suffer: Emotional Suppression, Stress Exposure, and Physiological Health Among Men Across the Life Course (2026) · cites this paper as O’Connor et al., 2009
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“As explained by O’Connor et al. (2009), behavioral and biological pathways can also mediate the effects of psychological factors on the inflammatory markers, such as regulation strategies.”
From Strong Enough to Suffer: Emotional Suppression, Stress Exposure, and Physiological Health Among Men Across the Life Course (2026) · cites this paper as O’Connor et al., 2009
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“We examined alternative explanations by statistically controlling for plausible demographic and biobehavioral confounders (29).”
From Clustering of depression and inflammation in adolescents previously exposed to childhood adversity (2012) · cites this paper as [29]
In the citing paper
“Based on prior work,12,45,46 we controlled for extraneous factors associated with inflammation.”
From Social Media Use and Its Link to Physical Health Indicators (2022) · cites this paper as [48]
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“Based on prior work (Horn et al., 2018; Lee and Way, 2019; O'Connor et al., 2009), we controlled for extraneous factors that have been associated with inflammation.”
From Social media use and systemic inflammation: The moderating role of self-esteem (2021) · cites this paper as O'Connor et al., 2009
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“Biomarker participants were also similar on most health-related characteristics, but were less likely to smoke (p < .01).”
From Socioeconomic Status Interacts with Conscientiousness and Neuroticism to Predict Circulating Concentrations of Inflammatory Markers (2017) · cites this paper as [40]
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“Love and colleagues (40) reported that the biomarker sample was comparable to the broader MIDUS II sample on age, sex, race/ethnicity, marital status, and income, although participants were more likely to have a college degree (p < .01).”
From Socioeconomic Status Interacts with Conscientiousness and Neuroticism to Predict Circulating Concentrations of Inflammatory Markers (2017) · cites this paper as [40]
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“Covariates Informed by prior literature (Hadley & Decaro, 2014; O’Connor et al., 2009; Wilunda, Massawe, & Jackson, 2013), we included a number of child, maternal, and household characteristics as covariates and potential confounders.”
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“Also carefully assessed and statistically controlled will be information about biobehavioral confounds of inflammation including alcohol consumption, smoking history, BMI, physical activity; and use of medications (antidepressants, statins, and NSAID) [32].”
Self-citationBereavement, Self-Reported Sleep Disturbances, and Inflammation: Results From Project HEART
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“Demographic variables including age, sex, race/ethnicity, education, caffeine consumption, obesity, and comorbid conditionswere included inmultiple regressionmodels as covariates because of theirwell-established impact on inflammationmarkers (32).”
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MethodStudent Debt and Cardiovascular Disease Risk Among U.S. Adults in Early Mid-Life
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“determined by screening urine test for substances; body mass index >35 kg/m2 because of the effects of obesity on proinflammatory cytokine activity (O’Connor et al., 2009) and also on risk for sleep disordered breathing; any clinically significant abnormalities on laboratory tests; clinically significant abnormalities…”
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“Because smoking and alcohol consumption are two major behavioral risk factors for inflammation and cardiovascular malfunction (O’Connor et al., 2009; O’Connor & Irwin, 2010), we controlled for these variables.”
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“The effects we observed may be confounded with other biobehavioral factors we did not measure that have been shown to be important for sleep and inflammation, such as SES, estrogen usage, statins, physical activity, and diet (O’Connor et al., 2009).”
BackgroundEveryday co-presence with a romantic partner is associated with lower C-reactive protein
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Self-citationSocioeconomic disparities in health: Changes in sleep quality and inflammation during bereavement
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“Lastly, the relationships between sleep, inflammation, and SES remained robust even after accounting for factors known to impact inflammatory outcomes [27] (see Tables S4 and S5).”
BackgroundMethodInfluentialTowards a multidimensional model of inflamed depression
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“Covariates accounted for extraneous variance in the inflammatory markers [41].”
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“These co-variates were based on previous literature suggesting that age and disease stage are related to inflammatory markers [57], and because they have been controlled for in our past studies relating inflammation to stress processes in breast cancer patients undergoing primary treatment…”
MethodMurphy, M. L. M., Sichko, S., Bui, T. Q., Libowitz, M. R., Shields, G. S., & Slavich, G. M. (2022) · Journal of Clinical Psychology · doi:10.1002/jclp.23417 · Cited by 10
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“Patients with lung cancer have multiple reasons for increased inflammation which may include smoking, obesity, and medical comorbidities in addition to cancer and its treatments (O’Connor et al., 2009).”
BackgroundThe Development of Posttraumatic Stress Disorder and Depression Symptoms in Iraqi Refugees
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“In addition to acculturation, biological variables such as inflammatory processes may also impact postmigration mental health in refugees (McCanlies et al., 2011; Miller et al., 2001; Passos et al., 2015).”
BackgroundCarlton, C. N., Garcia, K. M., Sullivan‐Toole, H., Stanton, K. J., McDonnell, C. G., & Richey, J. A. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100366 · Cited by 13
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“…for participant age (in years), BMI, medical comorbidities (Charlson Comorbidity Index score), race/ethnicity (ethnic minority status), and time since medical treatment completion, given their likelihood to influence immune and neuroendocrine functioning (Nicolson, 2008; O’Connor et al., 2009).”
BackgroundSelf-citationTaub, C. J., Diaz, A., Blomberg, B. B., Jutagir, D. R., Fisher, H. M., Gudenkauf, L. M., Lippman, M. E., Hudson, B. I., & Antoni, M. H. (2022) · Psychosomatic Medicine · doi:10.1097/psy.0000000000001109 · Cited by 9
“tory markers (24,25), and included age, disease stage, days since surgery,”
BackgroundEmployment and family income in psychological and immune outcomes during bereavement
Paoletti, J., Chen, M. A., Wu‐Chung, E. L., Brown, R. L., LeRoy, A. S., Murdock, K. W., Heijnen, C. J., & Fagundes, C. P. (2023) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2023.106024 · Cited by 9
Cytokines in Schizophrenia: Hope or Hype?
Koola, M. M. (2016) · Indian Journal of Psychological Medicine · doi:10.4103/0253-7176.178766 · Cited by 9
“[19] Medications commonly prescribed for people with schizophrenia including but not limited to selective serotonin reuptake inhibitors,[8,20] aspirin,[21] statins,[22] and antihypertensives[23] influence cytokines.”
BackgroundSichko, S., Bui, T. Q., Vinograd, M., Shields, G. S., Saha, K., Devkota, S., Alvarez, H. A. O., Carroll, J., Cole, S. W., Irwin, M. R., et al. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100334 · Cited by 9
“…had to be free of factors that are known to in fl uence in fl ammation, including: past or current in fl ammatory illness, major sleep disturbance, tobacco use, prescription drug use, excessive caffeine use (i.e., > 8 beverages per day), or a body mass index of (cid:1) 30 (O'Connor et al., 2009).”
BackgroundSelf-citationPulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis
Dong, K., Huh, S. M., Lam, G. Y., Jang, J., Franciosi, A. N., Wilcox, P., & Quon, B. S. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2022.12.013 · Cited by 9
The role of interpersonal processes in shaping inflammatory responses to social-evaluative threat
John‐Henderson, N. A., Stellar, J. E., Mendoza‐Denton, R., & Francis, D. D. (2015) · Biological Psychology · doi:10.1016/j.biopsycho.2015.07.011 · Cited by 8
Translational Implications of Inflammatory Biomarkers and Cytokine Networks in Psychoneuroimmunology
Yan, Q. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-071-7_6 · Cited by 8
Miller, B. J., McCall, W. V., McEvoy, J. P., & Lu, X. (2021) · Psychiatry Research · doi:10.1016/j.psychres.2021.114195 · Cited by 8
Partner’s Perceived Social Support Influences Their Spouse’s Inflammation: An Actor–Partner Analysis
Landvatter, J., Uchino, B. N., Smith, T. W., & Bosch, J. A. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19020799 · Cited by 8
“Standard variables including age, gender, body mass, and medications linked to chronic conditions were statistically adjusted for [37,42,43].”
BackgroundPiber, D., Olmstead, R. E., Cho, J. H., & Irwin, M. R. (2023) · SLEEP · doi:10.1093/sleep/zsad130 · Cited by 14
Self-citationTranslation of Psychoneuroimmunology Into Personalized Medicine: A Systems Biology Perspective
Yan, Q. (2011) · Personalized Medicine · doi:10.2217/pme.11.69 · Cited by 9
Intelligence and Interleukin-6 in Older Adults: The Role of Repetitive Thought
Segerstrom, S. C., Reed, R. G., & Scott, A. B. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000479 · Cited by 8
Mean affect and affect variability may interact to predict inflammation
Jones, D. R., Ruiz, J. M., Schreier, H. M. C., Allison, M., Uchino, B. N., Russell, M. A., Taylor, D. J., Smith, T. W., & Smyth, J. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.01.008 · Cited by 7
Vagnini, K. M., Boylan, J. M., Adams, M., & Masters, K. S. (2024) · Annals of Behavioral Medicine · doi:10.1093/abm/kaae032 · Cited by 10
“Covariate selection followed the recommendations of O’Connor et al. [45].”
MethodArgueta, D. L., Brice, K. N., Wu‐Chung, E. L., Chen, M. A., Lai, V., Paoletti, J., Denny, B. T., Green, C., Medina, L. D., Schulz, P. E., et al. (2024) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2024.107140 · Cited by 8
Sleep Quality and Inflammation in Married Heterosexual Couples: an Actor-Partner Analysis
Uchino, B. N., Scott, E. E., de Grey, R. G. K., Hogan, J. N., Trettevik, R., Cronan, S. B., Smith, T. W., & Bosch, J. A. (2019) · International Journal of Behavioral Medicine · doi:10.1007/s12529-018-09763-2 · Cited by 7
Avoidance-related EEG asymmetry predicts circulating interleukin-6.
Shields, G. S., & Moons, W. G. (2015) · Emotion · doi:10.1037/emo0000120 · Cited by 7
“6 O’Connor et al. (2009) recommend potentially controlling for former smoking status.”
InfluentialSalomon, R. E., Tan, K. R., Vaughan, A., Adynski, H., & Muscatell, K. A. (2019) · International Journal of Nursing Studies · doi:10.1016/j.ijnurstu.2019.103419 · Cited by 9
Jones, E. J., & Schreier, H. M. C. (2022) · Annals of Behavioral Medicine · doi:10.1093/abm/kaac008 · Cited by 7
Discrimination and Cognition in Midlife Black Women: The Roles of Social Support and Spirituality
Dixon, J. S., Wang, D., & Ready, R. E. (2023) · The Journals of Gerontology Series B · doi:10.1093/geronb/gbad201 · Cited by 6
Boyle, C. C., Cho, H. J., Eisenberger, N. I., Olmstead, R., Sadeghi, N., Castillo, D., & Irwin, M. R. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03752-2 · Cited by 6
Self-citationEggart, M., Valdés‐Stauber, J., Müller-Oerlinghausen, B., & Heinze, M. (2023) · Brain Sciences · doi:10.3390/brainsci13020353 · Cited by 6
On the pursuit of reproducibility: the importance of large sample sizes in psychoimmunology
Rengasamy, M. L., Moriarity, D. P., & Price, R. B. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03244-3 · Cited by 6
Bhattacharya, S., Gaur, P., Kant, S., Kushwaha, R., Singh, G., & Pandey, S. (2020) · Journal of Cancer Research and Therapeutics · doi:10.4103/jcrt.jcrt_632_18 · Cited by 8
Al-Agam, A. N. M., Obeiad, A. W., Alzughaibi, M. A. K., Al-Hindy, H. A.-A. M., & Alhaideri, A. F. (2021) · Iranian Rehabilitation Journal · doi:10.32598/irj.19.4.1619.1 · Cited by 6
Is Relapse in Schizophrenia an Immune-Mediated Effect?
Miller, B. J., & Buckley, P. F. (2012) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.10.2.115 · Cited by 6
Suarez, E. C. (2012) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780195394399.013.0010 · Cited by 6
Gender Differences in Biological Function in Young Adulthood: An Intragenerational Perspective
Jackson, M. I., & Short, S. E. (2018) · RSF The Russell Sage Foundation Journal of the Social Sciences · doi:10.7758/rsf.2018.4.4.06 · Cited by 6
“…j o u r n a l o f t h e s o c i a l s c i e n c e s respondents with very high levels of CRP (typically considered to be above 10 mg/L) are often excluded from analyses because of the possibility that these levels reflect acute (rather than chronic or systemic) inflammation (O’Connor et al. 2009).”
BackgroundStephenson, A. R., Chat, I. K.-Y., Bisgay, A., Coe, C. L., Abramson, L. Y., & Alloy, L. B. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.035 · Cited by 6
Psychological well‐being and salivary markers of inflammation: The moderating effect of age
Lee, S., Chey, J., Ahn, W., Woo, C., Youm, Y., Kim, H., Oh, N., Park, H.-Y., Gim, S., Lee, E., et al. (2022) · Applied Psychology Health and Well-Being · doi:10.1111/aphw.12389 · Cited by 5
Inflammatory and Oxidative Stress Biomarkers in the Elderly, the Birjand Longitudinal Aging Study
Moshtagh, M., Moodi, M., Moezi, S. A., Sharifi, F., & Khazdair, M. R. (2023) · BioMed Research International · doi:10.1155/2023/4683542 · Cited by 5
“According to studies findings, the surge of inflammatory markers like interleukin- (IL-) 6 and C-reactive protein (CRP) is related to the number of cigarettes consumed in the life period [15, 16].”
BackgroundTobón, A. L., Condon, E. M., Slade, A., Holland, M. L., Mayes, L. C., & Sadler, L. S. (2023) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0000000000001180 · Cited by 5
“We included child sex as a covariate because prior research demonstrates that sex may influence inflammatory function.(28) We adjusted for child race and ethnicity because of demographic differences between MTB-ESA intervention and control groups, and we controlled for child age as this is also a proxy for time since…”
MethodBurns, C., Hejl, C., & Szabo, Y. Z. (2024) · Journal of Child & Adolescent Trauma · doi:10.1007/s40653-023-00594-2 · Cited by 6
“These were selected based on recommendations for research with inflammation in health research (O’Connor et al., 2009; Szabo & Slav-ish, 2021).”
Psychosocial predictors of the innate immune response to influenza vaccination
Kuhlman, K. R., Radin, A. S., Cole, S. W., & Bower, J. E. (2024) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2024.106989 · Cited by 5
Self-citationBenmhammed, H., Lamtai, M., Mesfioui, A., Nassiri, A., Mouden, S., Bikri, S., & Hessni, A. E. (2024) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-024-01584-z · Cited by 5
Mengelkoch, S., Alley, J. C., Cole, S. W., & Slavich, G. M. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.11.024 · Cited by 5
“Moreover, they lived with their biological mothers, had a body mass index ≤ 30, spoke English, and were free of factors known to influence inflammation, including: inflammatory disorders, major sleep disturbance, prescription drug use, and excessive caffeine use (O ’ Connor et al., 2009).”
Accuracy and Positivity in Adolescent Perceptions of Parent Behavior
Human, L. J., Chan, M., Ifthikhar, R., Williams, D. S., DeLongis, A., & Chen, E. (2016) · Social Psychological and Personality Science · doi:10.1177/1948550616660590 · Cited by 5
“We present the results with covariates included to be consistent with recommended practices (O’Connor et al., 2009), but all effects reported below hold without their inclusion and these covariates did not significantly moderate any effects presented later.”
MethodReis, J. C., Travado, L., Seixas, E., Sousa, B., & Antoni, M. H. (2022) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2022.100433 · Cited by 6
Lee, C., & Whooley, M. A. (2023) · International Journal of Methods in Psychiatric Research · doi:10.1002/mpr.1968 · Cited by 5
“We included demographic, lifestyle, and clinical variables that fulfilled the above criteria based on the empirical evidence (O’Connor et al., 2009; Smith et al., 2018).”
Method
Metadata
- Authors
- O’Connor, M.-F., Bower, J. E., Cho, H. J., Creswell, J. D., Dimitrov, S., Hamby, M. E., Hoyt, M. A., Martin, J. L., Robles, T. F., Sloan, E. K., Thomas, K. S., & Irwin, M. R.
- Affiliations
- University of California, Los Angeles (US)
- Carnegie Mellon University (US)
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 23
- Issue
- 7
- Pages
- 887-897
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2749909
- OpenAlex
- W2131056323
- Cited by
- 500
- References
- 178
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 23 · 2023: 34 · 2022: 52 · 2021: 43 · 2020: 39 · 2019: 37 · 2018: 31 · 2017: 27 · 2016: 29 · 2015: 30 · 2014: 22 · 2013: 25 · 2012: 34
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG026364, R01AG034588, K23AG028452, P30AG028748, K01AG028404)
- National Heart, Lung, and Blood Institute (R01HL079955)
- National Institute of Mental Health (T32MH019925, T32 MH 19925, T32MH018399)
- National Cancer Institute (R01CA119159)
- National Center for Research Resources (M01RR000865)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- circulating inflammatory markers, biobehavioral factors, psychosocial factors, inflammation, confounding variables, control variables, exclusion criteria, age and sex effects, hormonal status, socioeconomic status, body mass index, physical activity, diet, caffeine, smoking, alcohol, sleep disruption, antidepressants, aspirin
- MeSH terms
- Anticholesteremic Agents, Antihypertensive Agents, Diet, Humans, Inflammation, Interleukins, Physical Fitness, Research Design, Risk Factors, Risk-Taking, Smoking, Social Class, Tumor Necrosis Factor-alpha, Biomarkers, Exercise, Epidemiologic Factors, Body Mass Index, Patient Selection, Antidepressive Agents, Second-Generation
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