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PubMed2005

Mediation analysis of a school-based drug prevention program: effects of Project ALERT.

This study used mediation analyses, implemented in a longitudinal structural equation modeling framework, to examine the mechanisms by which a social-influence-based school drug use prevention program (Project ALERT) achieved its effects on past month cigarette use and alcohol misuse. Participants were 4277 South Dakotan middle-school students (2554 treatment and 1723 control) measured at baseline and 1 year later on past month cigarette use and alcohol misuse, as well as cigarette- and alcohol-related mediating variables targeted by the Project ALERT curriculum (i.e., resistance self-efficacy, positive and negative beliefs about use, and peer influence). Results for cigarettes showed that all hypothesized mediating variables were significant mediators of ALERT's effect on intentions to smoke and past month cigarette use, with peer influence being the strongest. Results for alcohol point to positive beliefs about the consequences of drinking as an important mediator for alcohol misuse. Taken together, the findings highlight an avenue for program improvement through increased impact on peer influence to use alcohol and drugs.

Adolescent↗

PubMed2005

Depressed mood and social support as predictors of quality of life in women receiving home health care.

We examined relationships among depressed mood, social support and quality of life in 58 medically ill low-income women 40 years and older receiving home health care. Analyses showed a negative relationship between depressed mood and quality of life (p's < or = 0.05). Positive relationships were found between number of people available for support and two of three quality of life domains as well as satisfaction with support and all three domains (p's < or = 0.05). Results also provided preliminary support that belonging to a church is related to emotional well-being (p = 0.039) and among those belonging to a church, recent increased activity was related to social/family well-being (p = 0.004). Mediational analyses revealed a cycle of depressed mood, dissatisfaction with social support, and loss of social support providers underlying the poor quality of life of many participants. This highlights the need to address the relationship between depression and social support when treating patients with chronic illness.

Adult↗

PubMed2006

Games researchers play--extreme-groups analysis and mediation analysis in longitudinal occupational health research.

OBJECTIVES: The study of causal processes using a longitudinal design is often hampered by two methodological problems. First, the lagged effects of a predictor variable on an outcome variable tend to be weak after control for a previous measure of this outcome. One approach that is advocated when effects are weak is to increase the extremeness of the study groups; this step often increases the significance and sizes of effects. Second, causal links are often mediated through third variables, and thus relatively complex mediational analyses are needed to understand the causal processes underlying particular associations. The present paper shows whether and when these two approaches are useful in longitudinal research. METHODS: The two approaches were evaluated using data from a three-wave study among 1251 newcomers from various Western countries (mean age 20.6 years, 59% female). RESULTS: Although the significances and effect sizes indeed increased with increasing extremeness of the study groups, extreme-groups analysis in the context of a longitudinal design may grossly bias findings. Cross-sectional applications of mediation analysis cannot provide evidence for any mediational model. Longitudinal models are better suited for examining mediation. CONCLUSIONS: Rather than using extreme-groups analysis to obtain significant effects across time, researchers should maximize the amount of change in their data by focusing on groups for which change can be expected. Especially multiphase longitudinal data sets offer good opportunities for analyzing mediation models.

Adult↗

PubMed2026

Handgrip strength and risk of common infections and sepsis: Two prospective cohorts with proteomic mediation analysis.

BACKGROUND: Recent evidence links adiposity with the risk of severe infections, but whether muscle strength may also be an independent risk factor is less studied. We investigated the association between handgrip strength and risk of common infections and sepsis and explored potential mediation by plasma proteomic biomarkers. METHODS: We analyzed data from 405,451 UK Biobank participants and replicated the main findings in 4474 Chinese adults from the Hong Kong Osteoporosis Study (HKOS). Baseline handgrip strength was measured by a dynamometer. Cox models were used to estimate its association with incidence of pneumonia, urinary tract infection (UTI), skin infection, and sepsis, adjusting for sociodemographic, lifestyle, and health-related factors. Mediation analyses were performed using 2912 plasma proteins in a UK Biobank subsample (n = 42,414) to identify biological pathways. RESULTS: In UK Biobank (median follow-up 13.6-15.3 years), lower handgrip strength was associated with significantly increased risk of pneumonia (hazard ratio per 5-kg decrement=1.10; 95% CI=1.09-1.11), UTI (1.10; 1.09-1.11), skin infection (1.05; 1.04-1.05), and sepsis (1.08; 1.07-1.10). Associations were largely consistent in HKOS, and the relative risks associated with low grip strength were generally most pronounced in underweight individuals. GDF15 and PLAUR were identified as the most important proteins which mediated 12-14% of these associations. CONCLUSION: Low handgrip strength is associated with increased risks of common infections and sepsis, particularly in underweight individuals, with partial mediation by proteins related to inflammation and immune-related pathways. Handgrip strength assessment may provide prognostic value beyond body mass index for clinical risk stratification.

Humans↗

PubMed2004

Violence-related outcomes of the D.A.R.E. plus project.

The objectives of this study were to examine outcomes of the Minnesota D.A.R.E. Plus Project on violence-related behaviors among middle school students and mediation analyses that test how the intervention was effective in reducing physical and verbal violence. Twenty-four schools were randomly assigned to the D.A.R.E. middle school curriculum, the D.A.R.E. Plus multicomponent intervention, or control. The study cohort completed a self-report questionnaire at baseline and two follow-ups. The results showed that boys had higher rates of violence and victimization than girls. The D.A.R.E. Plus program was more effective in preventing violence among boys than among girls. It appears that the small behavioral effect that D.A.R.E. Plus did demonstrate on physical and verbal violence among boys was entirely mediated by a decrease of norms that support violence, an increase in outcome expectancies about being violence-free, and an increase in parental consequences for fighting.

Adolescent↗

PubMed2026

Investigating the mechanisms linking vitamin D to coronary artery disease: A mediating proteomics Mendelian randomisation study.

Coronary artery disease (CAD) is a leading cause of mortality and morbidity globally, with its elevated rates of disability and death posing a significant public health concern. Vitamin D is a crucial bioactive compound involved in numerous physiological processes and has garnered considerable interest due to its potential health benefits. The association between vitamin D and CAD has been a prominent focus of scholarly investigation. However, there remains considerable debate regarding whether vitamin D confers protective effects against CAD, and the underlying mechanisms by which vitamin D influences CAD remain inadequately understood. Mendelian randomization analysis was performed using large-scale genome-wide association study data to examine the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and CAD. Plasma proteomics data were subsequently employed for mediation analysis, followed by enrichment analysis to identify intermediary metabolic or signaling pathways through which serum 25(OH)D may mediate the onset and progression of CAD. The Mendelian randomization analysis indicated that higher serum 25(OH)D levels were associated with a reduced risk of CAD (odds ratio [95% confidence interval]: 0.799 [0.643-0.993], P = .043). No evidence of pleiotropy (P = .949) or heterogeneity (P = .630) was observed in the results. The protein-mediated analysis identified 19 plasma proteins, including Serine/threonine-protein kinase TBK1, membrane associating domain domain-containing protein 2, and interleukin-17D, as key mediators through which reduced vitamin D levels contribute to the development of CAD. The mediation effects ranged from 4.85 to 34.49%. Following the identification of these 19 mediating proteins, 59 intermediary pathways were further pinpointed through which serum vitamin D influences CAD risk. Increased levels of 25(OH)D may reduce the risk of CAD. Further, plasma proteomics-mediated analyses have uncovered potential mechanisms through which 25(OH)D influences the development of CAD, offering a detailed framework for understanding the relationship between vitamin D deficiency and CAD progression. This provides novel evidence to support the recommendation of appropriate vitamin D supplementation as part of lifestyle guidance for CAD patients.

Coronary Artery Disease↗

PubMed2026

Plasma Multiomics Links Early-Life Adversity to Disease and Cardiometabolic Health: A Population-Based Cohort Study.

BACKGROUND: Childhood adversity (CA) is associated with increased cardiovascular and cardiometabolic risk, but the molecular mechanisms remain unclear. We aimed to identify CA-related metabolomic and proteomic signatures and evaluate their roles in linking CA to incident diseases. METHODS: This prospective cohort study included 153 225 participants aged 48 to 64 years. CA was assessed using the Childhood Trauma Screener-5, capturing cumulative (0-5 domains) and individual adversity exposures. Plasma metabolomics and proteomics data were integrated to derive CA-related molecular signatures. Cox proportional hazards model was used to evaluate associations between CA, molecular signatures, and 58 incident diseases and mortality. Mediation analyses quantified the role of multiomics signatures. RESULTS: Each additional CA domain was associated with higher risk of 49 of 58 incident diseases (hazard ratios [HRs], 1.024-1.338) and a 7.3% higher all-cause mortality risk. Focusing on cardiometabolic health, the CA-related metabolic and proteomic signatures were independently associated with incident disease. Per 1-SD increase in the cumulative CA metabolic signature, the highest observed HR was 1.313 (95% CI, 1.278-1.349) for incident diabetes, and the risk for hypertension was also increased (HR, 1.136 95% CI, 1.114-1.159). Similarly, the proteomic signature was strongly associated with incident diabetes (HR, 1.645 95% CI, 1.489-1.818) and hypertension (HR, 1.223 95% CI, 1.155-1.295). The cumulative CA metabolic and proteomic signatures mediated up to 25.5% and 46.8% of the association with hypertension, respectively. CONCLUSIONS: CA is associated with a broad spectrum of diseases and mortality, with particularly strong links to cardiometabolic health. Multiomics signatures partially mediated these associations.

Humans↗

PubMed1997

Social relationships and immune processes in HIV seropositive gay and bisexual men.

This three-year longitudinal study assessed the association between social relationships and human immunodeficiency virus (HIV) progression in individuals at risk for morbidity and mortality due to acquired immune deficiency syndrome (AIDS). Two-hundred five HIV seropositive men without AIDS completed measures of social integration and loneliness at baseline. Blood samples used to assess CD4 T-lymphocyte levels were collected at baseline and at six-month intervals for a three-year follow-up period. Contrary to expectation, lower levels of baseline loneliness predicted more rapid declines in CD4 levels over the follow-up period. This association was independent of baseline CD4 values, negative affect, and health practices. A series of mediational analyses revealed that sexual behavior, medication use, bereavement, coping, and a number of other variables were not mechanisms through which loneliness affected the immune system. Loneliness was not associated with time to AIDS diagnosis or time to AIDS-related mortality. These findings are consistent with the emerging view that social relationships can have deleterious, as well as protective, influences on health outcomes.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Effectiveness of a community-based advocacy and learning program for hmong refugees.

The effectiveness of a community-based advocacy and learning intervention for Hmong refugees was assessed using a comprehensive, multi-method strategy, which included a within-group longitudinal design with four data collection points and in-depth qualitative recruitment and post-intervention interviews. The intervention's impact on five aspects of refugee well-being was examined: Participants' psychological well-being, quality of life, access to resources, English proficiency, and knowledge for the U.S. citizenship exam. Twenty-eight Hmong adults and 27 undergraduate students participated together in the intervention, which had two major components: (1) Learning Circles, which involved cultural exchange and one-on-one learning opportunities for Hmong adults, and (2) an advocacy component that involved undergraduates advocating for and transferring advocacy skills to Hmong families to increase their access to resources in their communities. Undergraduate paraprofessionals and Hmong participants worked together for 6-8 hr per week for 6 months. Growth trajectory analysis revealed promising quantitative findings. Participants' quality of life, satisfaction with resources, English proficiency, and knowledge for the U.S. citizenship test increased and their levels of distress decreased over the course of the intervention. Mediating analyses suggested that participants' increased quality of life could be explained by their improved satisfaction with resources. Qualitative data helped to support and explain the quantitative data, as well as providing insight into other outcomes and processes of the intervention. Policy, practice, and research implications are discussed.

Adolescent↗

PubMed2005

Intervention groups for adolescents with conduct problems: is aggregation harmful or helpful?

Past research has suggested that the aggregation of deviant peers during treatment may cause harmful effects (T. J. Dishion, J. McCord, & F. Poulin, 1999). This study compared the effectiveness of problem-solving skills training groups in which all members had conduct problems ("pure" group condition) with groups that consisted of adolescents with and without behavior problems ("mixed" group condition). Participants were 139 sixth- and seventh-graders (mean age = 12.7; 63% male; 55% White) enrolled at public middle schools. Pre-, post-, and 6-month follow-up data were collected, along with intervention process variables. Results showed that, contrary to the deviancy training hypothesis, adolescents in the pure-group condition engaged in more adaptive in-session behavior and received lower scores on the parent and teacher ratings of externalizing behavior at postintervention than those in the mixed-group condition. Mediation analyses showed that the deviancy training that occurred in the mixed-group condition accounted for their worse postintervention scores, findings consistent with the deviancy training hypothesis.

Achievement↗

PubMed2005

The role of stress-induced cortisol in the relationship between depression and decreased bone mineral density.

BACKGROUND: This study was designed to test the hypothesis that cortisol mediates the relationship between bone density and depression in postmenopausal women. METHODS: Nineteen women aged 52-79 who had been assessed for bone mineral density by dual-energy x-ray absorptiometer (DEXA) were evaluated for depression and anxiety. Diurnal and stress-induced measures of salivary cortisol were obtained during the following week and at a laboratory session involving a speech task. RESULTS: Nine volunteers reported depression while 10 were never depressed. Ever depressed women had significantly lower total lumbar and right femur DEXA Z scores than never depressed (t(17) = 2.5, p = .019 and t(17) = 2.06, p = .05, respectively). Ever depressed women demonstrated a significant increase in salivary cortisol (area under the curve (AUC) = 27.83, SD = 37.64) compared to never depressed women (AUC = -13.34, SD = 19.55) (t(17) = -3.041, p = .007) during a psychological challenge. There were significant inverse relationships between salivary cortisol AUC values and bone density Z scores at every measured bone site. Mediation analyses suggest that 51 - 67% of the association between depression and bone density could be attributed to stress-induced changes in cortisol. CONCLUSIONS: Cortisol hypersecretion in response to stress may, in part, explain the impact of depression on bone density in post-menopausal women.

Absorptiometry, Photon↗

PubMed2026

Potential contribution of the microbiota-gut-brain axis to doxorubicin-associated cognitive impairment: Mechanisms, evidence, and therapeutic opportunities.

Chemotherapy-induced cognitive impairment (CICI), often termed chemobrain, is a clinically important complication of cancer treatment that can affect memory, attention, executive function, and processing speed during and after therapy. Doxorubicin is of particular mechanistic interest because brain parenchymal exposure is limited, yet preclinical studies consistently identify neuroinflammatory, oxidative, vascular, and synaptic abnormalities after treatment. This critical narrative review evaluates whether intestinal injury and disruption of the microbiota-gut-brain axis may contribute to these central effects. Preclinical evidence indicates that doxorubicin can alter microbial community structure, injure the intestinal barrier, modify SCFA-associated taxa or predicted functions, alter selected metabolite profiles, and promote systemic inflammatory and metabolic signaling. These peripheral changes could interact with brain endothelial cells, glia, mitochondria, hippocampal neurogenesis, and synaptic-plasticity pathways. However, the proposed doxorubicin-gut-brain pathway remains a predominantly preclinical and incompletely tested framework. No longitudinal human study has yet established, within the same patients, the temporal sequence linking doxorubicin exposure, microbiome or metabolome changes, systemic inflammation, and objective cognitive outcomes. Existing animal studies also vary in dose, regimen, tumor context, sampling time, microbiome methodology, and control of behavioral or microbiological confounders, while causal rescue experiments remain limited. Key priorities are therefore longitudinal human cohorts with pretreatment baselines and repeated multi-omics and cognitive assessments; animal studies that test temporal precedence and causal rescue or pathway blockade in the same model; mediation analyses that determine whether microbial or metabolic changes lie between treatment and cognitive dysfunction; and mechanism-informed clinical trials that demonstrate target engagement, cognitive benefit, oncology safety, and preservation of antitumor efficacy. Microbiome-directed interventions are promising but remain investigational for doxorubicin-associated CICI.

blood–brain barrier↗

PubMed2002

Clinical depression and inflammatory risk markers for coronary heart disease.

Despite mounting evidence that psychiatric depression heightens risk for cardiac morbidity and mortality, little is known about the mechanisms responsible for this association. The present study examined the relation between depression and the expression of inflammatory risk markers implicated in the pathogenesis of coronary heart disease (CHD). One hundred adults were enrolled (68% women, 48% Caucasian, 48% African-American, mean age 30 +/- 2 years). Fifty subjects met the diagnostic criteria for clinical depression; the remaining 50 were demographically matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or regular medication regimen aside from oral contraceptives. The depressed subjects exhibited significantly higher levels of the inflammatory markers C-reactive protein (3.5 +/- 0.5 vs 2.5 +/- 5 mg/L, p = 0.04) and interleukin-6 (3.0 +/- 0.3 vs 1.9 +/- 0.2 pg/ml, p = 0.007) compared with control subjects. Mediational analyses aimed at identifying the pathways contributing to this association revealed that neither cigarette smoking nor subclinical infection with cytomegalovirus or Chlamydia pneumoniae had been responsible. However, depressed subjects exhibited greater body mass than control subjects, and analyses were consistent with adiposity accounting for a portion of the relation between clinical depression and increased expression of inflammatory markers. These findings indicate that in otherwise healthy adults, depression is associated with heightened expression of inflammatory markers implicated in the pathogenesis of CHD. Increased body mass appears to be partially, although not completely, responsible for this relation.

Adult↗

PubMed2001

Facial mimicry and emotional contagion to dynamic emotional facial expressions and their influence on decoding accuracy.

The present study had the goal to assess whether individuals mimic and show emotional contagion in response to relatively weak and idiosyncratic dynamic facial expressions of emotions similar to those encountered in everyday life. Furthermore, the question of whether mimicry leads to emotional contagion and in turn facilitates emotion recognition was addressed. Forty-one female participants rated a series of short video clips of stimulus persons expressing anger, sadness, disgust, and happiness regarding the emotions expressed. An unobtrusive measure of emotional contagion was taken. Evidence for mimicry was found for all types of expressions. Furthermore, evidence for emotional contagion of happiness and sadness was found. Mediational analyses could not confirm any relation between mimicry and emotional contagion nor between mimicry and emotion recognition.

Adult↗

PubMed2000

Intermediate markers as surrogate endpoints in cancer research.

Because studies with surrogate cancer endpoints can be smaller, faster, and substantially less expensive than those with frank cancer outcomes, the use of surrogate endpoints is undeniably attractive. This attractiveness is likely to grow in coming years as the rapidly advancing discoveries in cell and molecular biology generate new therapies requiring testing and new markers that could plausibly serve as surrogates for cancer. Surrogate endpoint studies can certainly be suggestive. They continue to play a legitimate role in phase II studies, and they may give the right answers about intervention effects on or exposure associations with cancer. The problem is the uncertainty attached to most potential surrogates. Except for those few surrogates that are both necessary for and developmentally relatively close to cancer, the existence of plausible alternative pathways makes inferences about cancer from many surrogates problematic. Merely being on the causal pathway to cancer does not in itself constitute surrogate validity. It is the totality of causal connections that is critical. There is, unfortunately, a fairly extensive history of quite plausible surrogate markers giving the wrong answer about various chronic disease therapies. There is no reason to believe that cancer surrogacy is immune to such inferential difficulties. This article is, in part, an invitation, even a plea, for researchers to carry out the investigations necessary to evaluate potential surrogates, particularly surrogate-cancer studies and intervention or exposure-surrogate-cancer mediation analyses. Such studies are needed to generalize from surrogate endpoint findings to cancer. There is, however, an implicit and perhaps unavoidable irony here: the large, long, expensive studies required to evaluate potential surrogates fully are precisely the studies that surrogates were designed to replace. The exposure dependence alluded to earlier complicates matters further: establishing validity for a given surrogate for one intervention or exposure vis-à-vis cancer does not necessarily translate into validity for another intervention or exposure. One can enhance the inferential strength of surrogacy by using further "downstream" markers. Results of trials with CIN3 as an endpoint are arguably more persuasive than those from intervention studies with HPV infection endpoints. Similarly, one could consider only the advanced adenoma (> or = 1 cm, villous elements, or high-grade dysplasia) as the primary endpoint in adenoma recurrence trials. The inferential gain, however, comes with substantial costs: studies with CIN3 endpoints must be much larger than those with HPV infection endpoints; adenoma recurrence trials with sufficient rates of recurrence of advanced adenomas must be five or six times larger than trials with any recurrent adenomas as endpoints. A law emerges here: in using surrogate endpoints, inferential certainty is directly associated with study cost. In other words, one gets what one pays for. The problems inherent in using surrogate endpoints need not be regarded as a cause for pessimism in cancer research. If anything, the limitations of surrogacy are reminders of the complexity of cancer causation and affirm the continued importance of large clinical trials and observational epidemiologic studies with explicit cancer endpoints.

Adenocarcinoma↗

PubMed1998

Attachment styles, emotion regulation, and adjustment in adolescence.

Attachment style differences in psychological symptomatology, self-concept, and risky or problem behaviors were examined in a community sample (N = 1,989) of Black and White adolescents, 13 to 19 years old. Overall, secure adolescents were the best-adjusted group, though not necessarily the least likely to engage in risky behaviors. Anxious adolescents were the worst-adjusted group, reporting the poorest self-concepts and the highest levels of symptomatology and risk behaviors. In contrast, avoidant adolescents reported generally high levels of symptomatology and poor self-concepts but similar levels of risk behaviors to those found among secures. Mediation analyses suggested that the observed differences in problem behaviors were at least partially accounted for by the differential experience of distress symptoms (primarily hostility and depression) and by social competence. Finally, patterns of attachment effects were similar across age, gender, and racial groups, with some important exceptions.

Adaptation, Psychological↗

PubMed1999

Commitment, pro-relationship behavior, and trust in close relationships.

The present work advances and tests an interdependence-based model of the associations among commitment, pro-relationship behavior, and trust. Findings from two longitudinal studies revealed good support for model predictions. Commitment-inspired acts such as accommodation and willingness to sacrifice provide diagnostic information regarding a partner's pro-relationship motives. Individuals come to trust their partners when they perceive that their partners have enacted pro-relationship behaviors, departing from their direct self-interest for the good of the relationship. The results of mediation analyses are consistent with a model of mutual cyclical growth in which (a) dependence promotes strong commitment, (b) commitment promotes pro-relationship acts, (c) pro-relationship acts are perceived by the partner, (d) the perception of pro-relationship acts enhances the partner's trust, and (e) trust increases the partner's willingness to become dependent on the relationship. Auxiliary analyses revealed that self-reported attachment style does not account for substantial variance beyond the features of interdependence that form the basis for the present model.

Adult↗

PubMed2002

The role of optimism in social network development, coping, and psychological adjustment during a life transition.

The authors investigated the extent to which social support and coping account for the association between greater optimism and better adjustment to stressful life events. College students of both genders completed measures of perceived stress, depression, friendship network size, and perceived social support at the beginning and end of their 1st semester of college. Coping was assessed at the end of the 1st semester. Greater optimism, assessed at the beginning of the 1st semester of college, was prospectively associated with smaller increases in stress and depression and greater increases in perceived social support (but not in friendship network size) over the course of the 1st semester of college. Mediational analyses were consistent with a model in which increases in social support and greater use of positive reinterpretation and growth contributed to the superior adjustment that optimists experienced.

Adaptation, Psychological↗