Estimating between- and within-individual variation in cortisol levels using multilevel models

Cortisol measures often are used to examine variation in hypothalamic-pituitary-adrenal axis (HPA) activity as well as broader patterns of differential health. However, substantial within-individual variation renders single cortisol measurements unreliable as estimates for probing differences between individuals and groups. A standard practice to clarify between-individual differences involves collecting multiple samples from each participant and then deriving person-specific averages. By ignoring information about variation at between- and within-individual levels, this technique impedes cross-study comparison of results, ignores data useful for future study design, and hinders the analysis of cross-level interactions. This report describes how multilevel approaches can simultaneously model between- and within-individual variation in diurnal cortisol levels without using crude averages. We apply these models to data from children in Nepal (n=29, 11-15 samples per child), Mongolia (n=47, 8-12 samples per child) and the US (n=1269, 1-6 samples per child). Using the Nepal data, we show how an analysis of crude time-adjusted aggregates does not detect an association between aggressive behavior and cortisol levels, while a multilevel analysis does. More importantly, we argue that the 'roadmap' to variation generated by these multilevel models provides meaningful information about the predictive accuracy--not just statistical significance--of relationships between cortisol levels and individual-level variables, such as psychopathology, age, and gender. The 'roadmap' also facilitates comparison between the results from different studies and estimation of the necessary number of cortisol measurements for future investigations.

[1]  Colm O'Muircheartaigh,et al.  The relative impact of interviewer effects and sample design effects on survey precision , 1998 .

[2]  M. Gunnar.  The role of glucocorticoids in anxiety disorders: A critical analysis. , 2001 .

[3]  D. Bates,et al.  Mixed-Effects Models in S and S-PLUS , 2001 .

[4]  M. Gunnar,et al.  Quality of care and temperament determine changes in cortisol concentrations over the day for young children in childcare , 2000, Psychoneuroendocrinology.

[5]  R. Yehuda,et al.  Low cortisol and risk for PTSD in adult offspring of holocaust survivors. , 2000, The American journal of psychiatry.

[6]  I. Janszky,et al.  Cortisol and vital exhaustion in relation to significant coronary artery stenosis in middle-aged women with acute coronary syndrome , 2002, Psychoneuroendocrinology.

[7]  C. Kirschbaum,et al.  Genetic factors, perceived chronic stress, and the free cortisol response to awakening , 2000, Psychoneuroendocrinology.

[8]  C. Worthman.  Hormones, Health, and Behavior: Epidemiology of human development , 1998 .

[9]  S. Tunn,et al.  Simultaneous measurement of cortisol in serum and saliva after different forms of cortisol administration. , 1992, Clinical chemistry.

[10]  M. van Eck,et al.  The Effects of Perceived Stress, Traits, Mood States, and Stressful Daily Events on Salivary Cortisol , 1996, Psychosomatic medicine.

[11]  M. Gunnar,et al.  Preventive intervention for maltreated preschool children: impact on children's behavior, neuroendocrine activity, and foster parent functioning. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[12]  A. Baum,et al.  Adrenocortical Responsiveness to Psychosocial Stress in Humans: Sources of Interindividual Differences , 1998 .

[13]  J. Smyth,et al.  Individual differences in the diurnal cycle of cortisol , 1997, Psychoneuroendocrinology.

[14]  I. Goodyer,et al.  Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology , 2001, British Journal of Psychiatry.

[15]  K. O'Connor,et al.  Hormones, Health, and Behavior , 2000 .

[16]  S Epstein,et al.  Does aggregation produce spuriously high estimates of behavior stability? , 1986, Journal of personality and social psychology.

[17]  I. Goodyer,et al.  Adrenal secretion during major depression in 8- to 16-year-olds, I. Altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation , 1996, Psychological Medicine.

[18]  T. Ollendick,et al.  The Developmental Psychopathology of Anxiety , 2001 .

[19]  B. Kudielka,et al.  Awakening cortisol responses are influenced by health status and awakening time but not by menstrual cycle phase , 2003, Psychoneuroendocrinology.

[20]  H. Raff,et al.  Late-night salivary cortisol as a screening test for Cushing's syndrome. , 1998, The Journal of clinical endocrinology and metabolism.

[21]  M. Flinn,et al.  Social economics of childhood glucocorticoid stress response and health. , 1997, American journal of physical anthropology.

[22]  C. Kirschbauma,et al.  Awakening cortisol responses are influenced by health status and awakening time but not by menstrual cycle phase , 2002 .

[23]  C. Kirschbaum,et al.  Increased free cortisol secretion after awakening in chronically stressed individuals due to work overload , 1998 .

[24]  X. Bertagna,et al.  Reliability of hormonal levels for assessing the hypothalamic-pituitary-adrenocortical system in clinical pharmacology. , 1994, British journal of clinical pharmacology.

[25]  L. Shahab.  Socioeconomic status and health , 2007 .

[26]  C. Kirschbaum,et al.  Heritability of Daytime Cortisol Levels in Children , 2003, Behavior genetics.

[27]  R. Rose,et al.  Definition of a responder: analysis of behavioral, cardiovascular, and endocrine responses to varied workload in air traffic controllers. , 1993, Psychosomatic medicine.

[28]  S. Simpson.  Endocrinology and Metabolism , 1948 .

[29]  John B. Willett,et al.  Questions and Answers in the Measurement of Change , 1988 .

[30]  J. Cacioppo,et al.  Marital Conflict in Older Adults: Endocrinological and Immunological Correlates , 1997, Psychosomatic medicine.

[31]  I. Heuser,et al.  Increased diurnal plasma concentrations of cortisone in depressed patients. , 2000, The Journal of clinical endocrinology and metabolism.

[32]  K. Grankvist,et al.  [Salivary cortisol measurement--better than plasma assays]. , 1990, Lakartidningen.

[33]  M. Eid,et al.  Cortisol and behavior: 2. Application of a Latent state-trait model to salivary cortisol , 1990, Psychoneuroendocrinology.

[34]  S. Cleary,et al.  Morning cortisol as a risk factor for subsequent major depressive disorder in adult women. , 2000, The British journal of psychiatry : the journal of mental science.

[35]  N. Nicolson,et al.  Salivary cortisol patterns in vital exhaustion. , 2000, Journal of psychosomatic research.

[36]  E. Adam,et al.  Relationship functioning and home and work demands predict individual differences in diurnal cortisol patterns in women , 2001, Psychoneuroendocrinology.

[37]  J. Smyth,et al.  Individual differences in the diurnal cycle of salivary free cortisol: a replication of flattened cycles for some individuals , 2001, Psychoneuroendocrinology.

[38]  A. Convit,et al.  Salivary cortisol day profiles in elderly with mild cognitive impairment , 2002, Psychoneuroendocrinology.

[39]  C. Kirschbaum,et al.  Burnout, perceived stress, and cortisol responses to awakening. , 1999, Psychosomatic medicine.

[40]  C. Kirschbaum,et al.  Increasing correlations between personality traits and cortisol stress responses obtained by data aggregation , 1997, Psychoneuroendocrinology.

[41]  C. Zahn-Waxler,et al.  Adrenocortical activity in at-risk and normally developing adolescents: Individual differences in salivary cortisol basal levels, diurnal variation, and responses to social challenges , 2001, Development and Psychopathology.

[42]  J. Singer,et al.  Applied Longitudinal Data Analysis , 2003 .

[43]  A. Erkanli,et al.  The Great Smoky Mountains Study of Youth. Goals, design, methods, and the prevalence of DSM-III-R disorders. , 1996, Archives of general psychiatry.

[44]  David Walker,et al.  Behavior Assessment System for Children (BASC) , 1999 .

[45]  Judith D. Singer,et al.  Using SAS PROC MIXED to Fit Multilevel Models, Hierarchical Models, and Individual Growth Models , 1998 .

[46]  A. Reiss,et al.  Diurnal salivary cortisol in pediatric posttraumatic stress disorder , 2002, Biological Psychiatry.

[47]  Alan Booth,et al.  Low salivary cortisol levels and externalizing behavior problems in youth , 2005, Development and Psychopathology.

[48]  J. Smyth,et al.  STRESSORS AND MOOD MEASURED ON A MOMENTARY BASIS ARE ASSOCIATED WITH SALIVARY CORTISOL SECRETION , 1998, Psychoneuroendocrinology.

[49]  R. Loeber,et al.  Low salivary cortisol and persistent aggression in boys referred for disruptive behavior. , 2000, Archives of general psychiatry.

[50]  Xiao-Hua Zhou,et al.  Statistical Computing Software Reviews Comparisons of Software Packages for Generalized Linear Multilevel Models , 1999 .

[51]  S Rosberg,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Circadian Cortisol Rhythms in Healthy Boys and Girls: Relationship with Age, Growth, Body Composition, and , 2022 .

[52]  R. Littell.  SAS System for Mixed Models , 1996 .

[53]  A. Raine,et al.  Biosocial bases of antisocial behavior: psychophysiological, neurological, and cognitive factors. , 1997, Clinical psychology review.

[54]  Anthony S. Bryk,et al.  Hierarchical Linear Models: Applications and Data Analysis Methods , 1992 .

[55]  M. Gunnar,et al.  Rising cortisol at childcare: relations with nap, rest, and temperament. , 2002, Developmental psychobiology.

[56]  Andrew Steptoe,et al.  Psychological, cardiovascular, and metabolic correlates of individual differences in cortisol stress recovery in young men , 2001, Psychoneuroendocrinology.

[57]  M L Johnson,et al.  Amplitude modulation of a burstlike mode of cortisol secretion subserves the circadian glucocorticoid rhythm. , 1989, The American journal of physiology.

[58]  C. Kirschbaum,et al.  Salivary cortisol in psychobiological research: an overview. , 1989, Neuropsychobiology.

[59]  Sheldon Cohen,et al.  Stable individual differences in physiological response to stressors: implications for stress-elicited changes in immune related health , 2003, Brain, Behavior, and Immunity.

[60]  Roel Bosker,et al.  Modeled Variance in Two-Level Models , 1994 .

[61]  Dennis Wallace,et al.  Analysis of repeated measures designs with linear mixed models. , 2001 .

[62]  T. Pollard,et al.  Use of cortisol as a stress marker: Practical and theoretical problems , 1995, American journal of human biology : the official journal of the Human Biology Council.

[63]  D. Hellhammer,et al.  The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders , 2000, Psychoneuroendocrinology.

[64]  G. Molenberghs,et al.  Linear Mixed Models for Longitudinal Data , 2001 .

[65]  H. Goldstein.  Multilevel Statistical Models , 2006 .

[66]  D. Stram,et al.  Variance components testing in the longitudinal mixed effects model. , 1994, Biometrics.

[67]  T. Lewis,et al.  Outliers in multilevel data , 1998 .

[68]  H. Asscheman,et al.  Increased salivary cortisol in severe dental anxiety. , 1992, Psychophysiology.

[69]  A. Shirom,et al.  Chronic burnout, somatic arousal and elevated salivary cortisol levels. , 1999, Journal of psychosomatic research.

[70]  Harvey Goldstein,et al.  Multilevel modelling of health statistics , 2001 .

[71]  C. Nemeroff,et al.  Cortisol concentrations in 12- to 18-Month-Old infants: stability over time, location, and stressor , 2003, Biological Psychiatry.

[72]  C. Worthman,et al.  Hormone measures in finger-prick blood spot samples: new field methods for reproductive endocrinology. , 1997, American journal of physical anthropology.

[73]  S. Decker.  Salivary Cortisol and Social Status among Dominican Men , 2000, Hormones and Behavior.

[74]  James P. Smith.  Socioeconomic Status and Health , 1998 .

[75]  R. Poland,et al.  Urinary cortisol and catecholamines in mothers of child cancer survivors with and without PTSD , 2002, Psychoneuroendocrinology.

[76]  D. Boomsma,et al.  Heritability of cortisol levels: review and simultaneous analysis of twin studies , 2003, Psychoneuroendocrinology.