Within the Biostatistics, Epidemiology, and Research Design (BERD) component of the Northwestern University Clinical and Translational Sciences Institute, we created a mentoring program to complement training provided by the associated Multidisciplinary Career Development Program (KL2). Called Research design Analysis Methods Program (RAMP) Mentors, the program provides each KL2 scholar with individualized, hands-on mentoring in biostatistics, epidemiology, informatics, and related fields, with the goal of building multidisciplinary research teams. From 2015 to 2019, RAMP Mentors paired 8 KL2 scholars with 16 individually selected mentors. Mentors had funded/protected time to meet at least monthly with their scholar to provide advice and instruction on methods for ongoing research, including incorporating novel techniques. RAMP Mentors has been evaluated through focus groups and surveys. KL2 scholars reported high satisfaction with RAMP Mentors and confidence in their ability to establish and maintain methodologic collaborations. Compared with other Northwestern University K awardees, KL2 scholars reported higher confidence in obtaining research funding, including subsequent K or R awards, and selecting appropriate, up-to-date research methods. RAMP Mentors is a promising partnership between a BERD group and KL2 program, promoting methodologic education and building multidisciplinary research teams for junior investigators pursuing clinical and translational research.

OBJECTIVES/SPECIFIC AIMS: There has been substantial research showing that there are race and sex differences on alcohol use. Similarly, race and sex disparities are also seen in a variety of different factors that impact drinking behaviors and other health outcomes. One of these factors of interest is Adverse Childhood Experiences (ACEs) which is associated with an increased risk for excessive alcohol use and the harmful effects of drinking. Several studies have shown that racial minorities and females have a greater risk of ACEs, which may be partly related to various structural factors (i.e. poverty) and social norms. Although there has been a substantial amount of research done on ACEs, very few studies have looked at how their interaction with race and sex can influence alcohol-related behaviors. METHODS/STUDY POPULATION: 1,509 participants who self-identified as either Black or White were recruited through a screening protocol at the NIAAA where they completed a series of questionnaires. We categorized the participants into two groups based on the Structured Clinical Interview for DSM-IV disorders: Alcohol Dependent individuals (N=921) with either a past and/or current diagnosis and Non-dependent individuals (N=588). ACEs exposure was assessed using the Childhood Trauma Questionnaire (CTQ). We looked at both total score and the 5 subscales: emotional abuse, physical abuse, sexual abuse, physical neglect, and emotional neglect. Drinking behaviors were assessed using a 90-day Timeline Followback interview and the Alcohol Use Disorder Identification Test (AUDIT). The non-dependent sample was 63% White and 55% male while the alcohol dependent sample was 47% White and 70% male. We tested the interaction effects using ANOVA. RESULTS/ANTICIPATED RESULTS: In the ND sample, there were significant race*sex*ACEs effects for average drinks per day with CTQ total score (P = 0.007), physical abuse (P = 0.005), and physical neglect (P = 0.003). There was also a 3-way interaction with physical neglect on heavy drinking days (P = 0.039) and a 2-way race*ACEs interaction on AUDIT total with physical abuse (P = 0.048). In the AD sample, there were significant 2-way race*ACEs interactions for three drinking outcomes: heavy drinking days with physical neglect (P = 0.009), AUDIT-Harmful Use subscore with CTQ total score (P = 0.028) and physical neglect (P = 0.001), AUDIT-Total score with CTQ total score (P = 0.007), physical abuse (P = 0.042), sexual abuse (P = 0.024), and physical neglect (P = 0.003). There were also 3-way interactions for AUDIT-Harmful use (P = 0.013) and AUDIT-Total scores (P = 0.011) with emotional abuse. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that there are both 2-way (race*ACEs) and 3-way (race*sex*ACEs) interaction effects on alcohol consumption and the related negative effects for both non-dependent and dependent samples. There were no sex*ACEs interaction effects in either sample implying that race may play a bigger role in differentiating drinking outcomes by ACEs across males and females. However, contrary to our expectations, race seemed to be protective factor for Black participants against both alcohol consumption and the negative effects despite having higher rates of ACEs exposure. Future analyses will explore personality measures as potential mediators of the relationship between ACEs and alcohol use. Also, analyses will look to see if there are any behavioral factors that may contribute to resiliency among minority populations.

OBJECTIVES/SPECIFIC AIMS: The ACT Network was developed by 46 members of the CTSA Program hubs in collaboration with NCATS to help investigators explore and validate feasibility of clinical studies in real-time using linked electronic health record data for cohort discovery. ACT is being disseminated nationally across the CTSA consortium. METHODS/STUDY POPULATION: Diffusion of Innovation Theory and Lean Start-Up principles inform dissemination strategies. Core materials were developed nationally and are being tailored to meet local CTSA dissemination norms. An advisory board, with expertise in communications, journalism, customer channel management, pharmaceutical commercialization and health IT entrepreneurship, is providing strategic advice to develop and refine dissemination strategies. Evaluation of dissemination methods will include network usage and web analytics for the ACT Network’s interactive digital content and log-in portal, and surveys-interviews of ACT users using the RE-AIM implementation framework. RESULTS/ANTICIPATED RESULTS: Formative research identified ACT’s primary value proposition for clinical researchers: “Explore patient populations in depth, in real time, from your desktop;” “Confirm study feasibility by iteratively testing and refining inclusion and exclusion criteria;” “Demonstrate feasibility in funding proposals and IRB submissions;” and “Identify collaborating sites for multi-site studies by searching for patients across the CTSA network.” Early dissemination metrics, including number-type of registered users, queriesperformed, and web analytics, will be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: Researchers nationwide face common barriers in accruing enough participants for clinical trials. The inability to identify the right number and type of people to participate often makes clinical trials slow and costly. Better cohort discovery at the protocol development phase is a necessary requirement. By end of 2018, the ACT Network will reach 60% of the CTSA consortium providing a new tool for investigators to improve the design and execution of clinical trials.

OBJECTIVES/SPECIFIC AIMS: Biostatistics and Epidemiology courses within clinical research or public health training programs are typically developed and taught separately. As a result, students may have trouble in their research outside the classroom, where biostatistical and epidemiological concepts must be well integrated. Case method teaching is a participant- and discussion-centered pedagogical approach that has been used in business and law schools for more than 50 years to improve student learning, yet has taken longer to be adopted in health professional schools. The case method is distinguished by presenting learners with a real-world problem without a single unique solution. Designed to mimic the constraints and incomplete information found in real life, it is an ideal approach for integrating multiple related disciplines. A team of Clinical and Translational Science (CTS) faculty from the Tufts CTSI collaborated to develop a new course that integrates epidemiology and biostatistics disciplines using the case method. METHODS/STUDY POPULATION: We developed an intermediate-level, case-based course integrating epidemiology and biostatistics topics using modern, real-world clinical examples. Recognizing the importance of technical skill building, this intermediate-level Tufts CTS course adopted a hybrid approach, incorporating lecture and in-class laboratory exercises, alongside cases. We surveyed CTS faculty to identify a set of core methodological competencies. These included randomized trials, case-control and cohort studies, confounding, effect modification, propensity scores, linear and logistic regression, and survival analysis. Faculty provided us with clinical questions and deidentified data sets corresponding to these competencies; we also reviewed publicly available data sets. RESULTS/ANTICIPATED RESULTS: CTS faculty collaborated to develop 10 cases (with accompanying data sets) from modern clinical research examples that illustrate the connections between epidemiology and biostatistical concepts. Each case contains a background section, a statement of the core problem, a data set with data dictionary, articles from the primary literature (often the publication of the data set) with discussion questions and in-class lab exercises (R programming). One case presents students with the challenge of whether acupuncture may be an effective therapy for pain associated with chronic headache. Through case activities, students gain experience weighing observational Versus experimental evidence, apply directed acyclic graph theory, and analyze clinical trial data. Qualitative evaluations in 2015 (pilot year) and 2016 indicate students preferred the integrated approach to separate courses, and found the integration facilitated application of methods to their independent research projects. Significant rewards for faculty include cross-disciplinary collaboration, sharpened teaching skills, and engaging with learners in a dynamic classroom environment. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite administrative and pedagogical challenges, a case-based, integrated curriculum offers rewards for faculty and students. The case method may be a useful pedagogical strategy to integrate other closely related topics or courses in translational science to better prepare scholars for the challenges of independent research.

OBJECTIVES/GOALS: We have evaluated the primary factors behind successful expansion of the predoctoral TL1 training grant at OHSU to all research-intensive universities in the state, evaluating the precepts that were key to integration. We also evaluate inclusion of social and behavioral sciences in clinical and translational science training, METHODS/STUDY POPULATION: OHSU contains three professional schools (medicine, nursing, and dentistry) as well as graduate studies in science. There are also three research-intensive universities in Oregon: Portland State University (PSU); Oregon State University (OSU) in Corvallis; and the University of Oregon (UO). We report evaluation of our 7-year experience with a predoctoral TL1 program and the precepts behind successful implementation of statewide outreach. We have tracked applicants from each university and program, trainee feedback, and success of the applicants as measured by persistence in research, inclusion of translational methods, additional training acquired, and subsequent research funding. We also evaluate participation by behavioral and social scientists. RESULTS/ANTICIPATED RESULTS: The predoctoral TL1 has included 40 scholars over 7 years, with 65% PhD graduate students and 35% MD students who pursue an additional research degree (PhD, MCR). Of PhD graduate students, the distribution is similar among universities: OHSU 31%, PSU 19%, OSU 27%, UO 23%. 38% of all graduate student trainees are in behavioral or social science. Key precepts behind success include: concentration on specific graduate programs at each university; implementing a common curriculum based on the MCR curriculum; interinstitutional mentor teams; leadership team that spans universities; required core TL1 activities; and a competitive application process with an interinstitutional review committee. Applicants are required to identify how translational science education enhances their research career. DISCUSSION/SIGNIFICANCE: Creating a statewide resource for TL1 translational science training has increased opportunities to expand translational research throughout Oregon through providing new opportunities to enhance excellence through disseminating resources and training across the universities.

OBJECTIVES/GOALS: The goals of this study are to 1) adapt a mindfulness-based intervention that supports the development of trust-promoting behaviors of OBGYN providers with patients who identify as Black women based on the input of providers and patients, and 2) assess the feasibility of implementation for OBGYN healthcare providers. METHODS/STUDY POPULATION: Goal 1: Focus groups will be conducted with members of the populations of providers and Black women patients in Alachua County, Florida to identify essential intervention content to complement the central component of mindfulness and spiritually based practices. This complementary content will serve to address the institutional and cultural context of the intervention setting. Goal 2: Providers will be recruited to participate in interviews about their perceptions of intervention feasibility. These aspects include recruitment potential, acceptability of the intervention content and delivery, implementation practicality, identification of appropriate outcomes, and identifying strategies to recruit Black women patients to participate in program evaluation. RESULTS/ANTICIPATED RESULTS: Goal 1: We will elicit the perspectives of providers and Black women patients regarding the respective roles and relationship of mindfulness and spirituality to increase trust-promoting behaviors with patients who are Black women. We also anticipate identifying additional content to complement the core intervention components that participants perceive as necessary to develop the knowledge, skills, and behaviors which convey the trustworthiness of providers to patients. Goal 2: We expect to gain key insights into intervention design, implementation, and evaluation feasibility from the perspective of providers. Interview data will be aggregated and qualitatively analyzed for themes pertaining to feasibility. DISCUSSION/SIGNIFICANCE: An intervention that builds on mindfulness and spiritual practice is an innovative approach to improving interpersonal outcomes in provider-patient relationships. By investigating the feasibility of such an intervention, we will gain insight into how to design and deliver a program to increase the trust-promoting behaviors of OBGYN providers.

Objectives/Goals: This scoping review examines how socioeconomic status (SES) and sociodemographic status (SDS) disparities are considered in transition interventions for congenital heart disease (CHD) patients. By identifying gaps, it aims to guide future research and interventions to address inequities in transitional care. Methods/Study Population: A systematic search of the literature was performed using PubMed, Scopus, and Web of Science. Literature was searched from January 1990 to October 2024 and revealed 823 articles. Upon initial screening, 71 duplicates, 76 non-SES focused articles, and an additional 128 irrelevant articles were excluded. A total of 548 full-text articles were reviewed. Articles that did not focus on transition interventions for CHD patients were excluded. Studies were analyzed for factors affecting care transitions with special attention to SDS and SES factors. SDS factors were defined as age, gender, race/ethnicity, and geographic location, while SES factors were defined as income level, education, employment status, and access to care. Results/Anticipated Results: Out of 548 articles reviewed, only 18 addressed SES factors, and 10 examined SDS factors in the transition from pediatric to adult care. The most common interventions were patient education (33%), care coordination (29%), and family support (21%), but they lacked tailoring to SES/SDS factors. Patients from low-income households were 50% more likely to experience care discontinuities and 40% less likely to participate in transition programs. Health literacy interventions were generic, overlooking socioeconomic differences. Tailored transition programs are needed to address low health literacy and financial barriers, potentially improving outcomes for disadvantaged patients in rural and underserved areas. Discussion/Significance of Impact: This review exposes the limited focus on SES and SDS disparities in CHD transition interventions. Disadvantaged patients face barriers like limited access to care and low health literacy. Developing tailored programs to address these gaps is crucial for enhancing transitions and improving long-term outcomes for vulnerable CHD patients.

OBJECTIVES/GOALS: Composition of demographics or image types in publicly available datasets may detract from deep learning (DL) diagnosis performance of underrepresented melanoma subtypes. We evaluate a DL model’s performance on melanoma subtypes (acral; head and neck) that have known association with poor prognosis. METHODS/STUDY POPULATION: We trained a CNN using a single InceptionV3 model for 30 epochs on dermoscopic images of pigmented lesions from the International Skin Imaging Collaboration (ISIC). The ISIC 2018 challenge training set had 10008 total images, with 1113 total nevi, 6705 total melanomas, 97 acral nevi, 10 acral melanomas, 256 head and neck (H&N) nevi, and 164 H&N melanomas. The non-acral test set had 117 melanomas and 200 nevi. The acral test set had 201 melanomas and 161 nevi. The H&N test set had 199 melanomas and 128 nevi. Area under the receiver operating curve (AUC) was calculated. The model was retrained with acral lesion oversampling (10x) and performance on the acral test set was re-evaluated. RESULTS/ANTICIPATED RESULTS: The model performed on the non-acral test with an AUC of 80.5%, on the acral test with an AUC of 76.3%, and on the head and neck test with an AUC of 83.8% After oversampling acral lesions within the training set, the model showed nearly the same performance as without oversampling on acral lesions: AUC of 75.6%. DISCUSSION/SIGNIFICANCE OF IMPACT: Diagnosis of high-risk melanoma subsets (acral; H&N) remains reliable despite underrepresentation during training, increasing validity for broad implementation of DL technology. Datasets for individual subtypes may not be warranted as findings suggest features may be learned from other skin lesions.

OBJECTIVES/SPECIFIC AIMS: Test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous intact GLP-1 after a mixed meal compared with valsartan. METHODS/STUDY POPULATION: Adults 18–80 years with pre-diabetes or type 2 diabetes and elevated blood pressure. RESULTS/ANTICIPATED RESULTS: We anticipate higher intact GLP-1 area under the cure after the meal when subjects receive sacubitril/valsartan compared with valsartan. DISCUSSION/SIGNIFICANCE OF IMPACT: Neprilysin inhibition may be a target for anti-diabetes therapy by decreasing degradation of GLP-1.

OBJECTIVES/GOALS: Engagement with art may reduce the social disconnection that accompanies chronic pain. Disaggregating specific from non-specific effects of arts-based programs is challenging. This study creates an experimental virtual museum to identify the separate and joint effects of art and social connection. METHODS/STUDY POPULATION: Two x two factorial experiment with repeated measures: (1) Artwork present condition is a virtual exhibition featuring paintings from the Google Arts & Culture collection; (2) Artwork absent condition is the same exhibition space but with the paintings removed; (3) Social connection condition asks participants to write about a situation in which they felt more socially connected to others; (4) Social disconnection conditions asks participants to write about a situation in which they felt more socially disconnected from others. Participants: (1) English language proficiency; (2) ≥18 years; (3) Chronic moderate to severe pain; (4) Lonely; (5) Has electronic device with internet connection. RESULTS/ANTICIPATED RESULTS: Participants will be recruited through a 3-month social media campaign conducted by StudyPages, a clinical trial recruitment and management platform. This study will evaluate the effects of virtual art exposure and social connectivity priming on pain and social disconnection reduction among lonely IWCP. Pre-intervention scores for pain intensity, pain unpleasantness, and perceived social disconnection will be compared to post-intervention scores. Secondary outcome measures include (a) Museum visit data (e.g., user movement, click, object interaction, open comments) and (b) perceptions about artwork. DISCUSSION/SIGNIFICANCE: Psychosocial support for IWCP may improve pain-related outcomes. This studys data will help to optimize virtual museum interventions and provides the first data we are aware of to evaluate the specific effects of art in virtual museum engagement to reduce pain and social disconnection among IWCP.

OBJECTIVES/GOALS: To improve the implementation of FDRs in translation research. Current statistical packages are hard to use and fail to adequately convey strong assumptions. We developed a software package that allows the user to decide on assumptions and choose the hey desire. We encourage wider reporting of FDRs for observed findings. METHODS/STUDY POPULATION: We developed a user-friendly R function for computing FDRs from observed p-values. A variety of methods for FDR estimation and for FDR control are included so the user can select the approach most appropriate for their setting. Options include Efron’s Empirical Bayes FDR, Benjamini-Hochberg FDR control for multiple testing, Lindsey’s method for smoothing empirical distributions, estimation of the mixing proportion, and central matching. We illustrate the important difference between estimating the FDR for a particular finding and adjusting a hypothesis test to control the false discovery propensity. RESULTS/ANTICIPATED RESULTS: We performed a comparison of the capabilities of our new p.fdr function to the popular p.adjust function from the base stats-package. Specifically, we examined multiple examples of data coming from different unknown mixture distributions to highlight the null estimation methods p.fdr includes. The base package does not provide the optimal FDR usage nor sufficient estimation options. We also compared the step-up/step-down procedure used in adjusted p-value hypothesis test and discuss when this is inappropriate. The p.adjust function is not able to report raw-adjusted values and this will be shown in the graphical results. DISCUSSION/SIGNIFICANCE OF IMPACT: FDRs reveal the propensity for an observed result to be incorrect. FDRs should accompany observed results to help contextualize the relevance and potential impact of research findings. Our results show that previous methods are not sufficient rich or precise in their calculations. Our new package allows the user to be in control of the null estimation and step-up implementation when reporting FDRs.

OBJECTIVES/GOALS: Misprescription of opioids has led to an epidemic of opioid use disorder (OUD). Females, among other differences, have increased susceptibility to the addictive properties of opioids. Yet, the exclusion of female subjects from many foundational studies on reward processing had hindered our ability to fully understand these disparities. METHODS/STUDY POPULATION: Estradiol (E2), a neuronal sex steroid, may play a role in sex differences in OUD. In this study, we used fadrozole, an aromatase inhibitor, to characterize the role of centrally produced E2 in heroin cue extinction memory retention (EMR, “remembering to forget”). Male and female rats self-administered heroin in a long-access paradigm (6hr/day) for 8 days, where a light/tone cue was co-presented with each infusion of heroin. This was followed by 1 day of cued extinction (6hr; light/tone but no heroin). Just prior to this session, fadrozole was infused into the basolateral amygdala (BLA) through implanted cannulas. The next day, subjects were given a cued EMR test (1hr; light/tone but no heroin) following another infusion of fadrozole. RESULTS/ANTICIPATED RESULTS: Females took more heroin than males (mg/kg) despite having similar active nose poke responding during acquisition. Regardless of aromatase inhibition, females had higher active nose pokes during the first hour of cued extinction relative to males. Both males and females treated with fadrozole in the BLA prior to cued extinction had impaired EMR on test, evidenced by increased active nose pokes and lower extinction indices relative to vehicle controls. Upon examination of the brains, we expect that aromatase inhibition will have impaired neuronal plasticity, as evidenced by decreases in numerous measures of plasticity. Furthermore, we expect to find sex differential expression of estrogen receptor (ER) subtypes throughout the BLA, suggesting a convergent sex effect of E2 on heroin EMR. DISCUSSION/SIGNIFICANCE: This study is the first to examine a behavioral role for central E2 in the BLA. Future studies will examine specific roles for ER subtypes on this behavior and synaptic plasticity. A better understanding of sex specific E2 signaling will promote further research on sex differences and allowing us to better address disparities in disorders like OUD.

ABSTRACT IMPACT: Current, complete, unbiased, and accurate information, which includes patient social and environmental context, is necessary to understand health outcomes. OBJECTIVES/GOALS: Literacy in technology empowers patients in improving their health. We hypothesize that by integrating this information into clinical information, obfuscated relationships may become apparent. To test this, we have combined technological literacy elements with clinical data and test results from patients at risk for severe COVID-19 reactions. METHODS/STUDY POPULATION: Zip level data was appended to approximately 55,000 clinical records of COVID-19 positive and negative patients with comorbidities linked to high illness severity (e.g., diabetes, heart disease). The patient zip code was matched to zip code level health and technology interest indicators. Health interest indicates the level of interest in health such as research, exercising, better dieting, preventive care, etc., and is ranked from 0 to 9. The technology interest indicator is a binary flag indicating technology adopters. These lifestyle factor data points were obtained from survey data and purchasing patterns using transactional and response information from self-reported sources. For each zip code, the index values were represented by a percentage of that population. RESULTS/ANTICIPATED RESULTS: There is a pronounced difference between urban and rural areas with respect to interest in health and technology. In neighborhoods where most residents are interested in both health and technology, the percentage of COVID-19 cases was smaller. A Wilcoxon signed-rank test indicated that the distributions were statistically different (p-value = 4.606e-06) when evaluating the low interest values for health and technology, and (p-value = 1.069e-09) when there was high interest in health and technology against COVID-19 results. In addition, the health and technology indicator variables are not correlated with income at the zip code level. At the low index values, interest in health and technology, the correlation was -0.0856, and at the high end, the correlation was -0.0436. DISCUSSION/SIGNIFICANCE OF FINDINGS: This result is significant for COVID-19 research because it describes a methodology for identifying patients who may be at higher risk for contracting the disease. This relationship was reflected in electronic health record data only after zip-level information was added. Moreover, this was true at across income levels.

OBJECTIVES/SPECIFIC AIMS: Describe the process used to develop job descriptions and how this translates into consistent hiring practices. Describe how competencies are used to provide transparency into professional development opportunities. Discuss planned incorporation of competencies into efforts to train the clinical research workforce. METHODS/STUDY POPULATION: These processes were developed at Duke, an academic medical center with over 2000 active clinical research protocols and 300 new clinical trials per year. Over 1000 employees were evaluated for mapping into clinical research positions, with 685 mapping into new research positions (makeup of workforce to be depicted). RESULTS/ANTICIPATED RESULTS: Prior to this initiative, the clinical research workforce was not well-defined. Through the mapping process, employees were mapped from over 80 different positions into 10 (figure), resulting in a workforce that allows for visible career ladders and greater opportunity for development. As the initiative evolves and grows to include competency-driven performance evaluations, training modules, and assessments, we anticipate the ability to see the relationship between the competencies and high-quality clinical research support. DISCUSSION/SIGNIFICANCE OF IMPACT: The use of competencies in the context of workforce development is not new, yet in clinical research, they provide a much-needed framework for an ever-evolving profession. This comprehensive use of competencies throughout a workforce development initiative is key to ensuring strong support of high-quality clinical research.

OBJECTIVES/GOALS: To evaluate whether the default mode network experiences age-related changes in functional connectivity and to identify these patterns of progression across seven decades of life. The overall goal is to evaluate whether quantifying these functional changes can serve as potential neurobiomarkers of aging for further quantitative genetic analyses. METHODS/STUDY POPULATION: Scans were performed at the RII on a 3T Siemens Trio scanner with an 8-channel head coil. Whole-brain, rsfMR imaging was performed using a gradient-echo EPI sequence sensitive to the BOLD effect (TE/TR = 30/3000 ms; flip angle = 90°; isotropic 1.72 mm2). Subjects were instructed to lie in dimmed light with their eyes open and try not to fall asleep. Image analysis was performed with FMRIB’s Software Library tools (www.fmrib.ox.ac.uk/fsl). Preprocessing of resting state data includes motion correction, brain extraction, spatial smoothing, and high-pass temporal filtering. Time series data was extracted from 9 DMN ROIs using FSL’s Featquery tool with 6mm radius spherical ROI masks created in Mango. After extraction, DMN connectivity was assess using structural equation modeling implemented in Amos 22.0 (IBM, Inc.). RESULTS/ANTICIPATED RESULTS: The exploratory SEM (eSEM) default mode network (DMN) model used consists of 9 regions of interest and 13 functional connectivity paths. The eSEM DMN model exhibited exceptional model fit to a primary resting state data set of 1169 subjects from the Genetics of Brain Structure project (1R01MH078111-01, David Glahn PI) with an RMSEA of 0.037. This model also had excellent model fit in 7 cohorts that were grouped by decade age (10s – RMSEA: 0.058, 20s – 0.051, 30s – 0.045, 40s – 0.048, 50s – 0.043, 60s – 0.035, 70s – 0.037). Analysis of the decade group-wise path coefficients identified 7 of the 13 paths (pC -> LMTG, pC -> PCC, PCC -> MPFG, PCC -> vACC, MPFG -> vACC, LIPL -> RIPL, LMTG -> RMTG) significantly negatively correlated with age-related changes. As early as the 1st decade of life, the functional connectivity within the DMN decreases. DISCUSSION/SIGNIFICANCE OF IMPACT: The DMN experiences progressive age-related decreases in connectivity, beginning in the first decade of life. Our results suggest that DMN path coefficients can serve as biomarkers of cognitive aging, which can then be used as quantitative traits for genetic analyses to identify genes associated with normal aging and age-related cognitive diseases.