ABSTRACT Among Alaska Natives in Alaska, Tuberculosis (TB) remains endemic in communities and is a leading cause of morbidity and mortality. Alaska Native communities continue to have the highest rates of TB disease in the U.S., and most TB cases occur in villages that remain far from health centers. The approach for diagnosing TB, which includes airlifting people with TB-related symptoms to regional centers for chest radiography and sputum collection, is difficult and expensive to implement effectively. Through our research in TB-endemic countries, we have identified screening and diagnostics testing modalities that are well-suited for efficient TB case finding in remote communities of Alaska. First, portable chest x-ray devices capture digital images that can be analyzed by computer-aided diagnostic (CAD) artificial intelligence programs for real-time interpretation. Second, as collecting sputum specimens has been a major diagnostic barrier for community-based diagnosis, we have recently demonstrated the high accuracy of tongue swab sampling for nucleic acid amplification testing of Mycobacterium tuberculosis (Mtb) among adults in South Africa. We also have strong data, using cultured Mtb specimens, demonstrating high accuracy on next-gen, high-throughput molecular testing systems, which have automated processes for analyzing thousands of samples at lower costs compared to conventional lab-based PCR systems. The objective in this application is to leverage our existing health infrastructure in south-western Alaska, expertise in clinical TB and diagnostic testing, and strong relationships with Alaska Native communities, to evaluate two novel community-based screening and diagnostic tools in TB-endemic regions of the United States. Our central hypotheses are: 1) portable chest x-ray devices using CAD interpretation will be accurate and feasible to implement in Alaska, and 2) tongue swab testing will be accurate when tested on an automated, high-volume molecular platform, as compared to conventional sputum-based molecular testing. We will test our hypotheses through the following two specific aims: (1) to determine if a portable, digital chest x-ray with real- time CAD can be accurate for TB screening, and feasible for use in community settings, within TB-endemic regions of Alaska; and (2) demonstrate the accuracy of tongue swab sampling with molecular testing using an automated high-throughput system, compared to current sputum-based molecular testing, among adults and children (≥5 years old) who have presumed pulmonary TB disease in Alaska. The research will be innovative by expanding the possible tools for community-based screening and diagnostic testing in TB-endemic communities in Alaska and elsewhere. This proposal is highly responsive to PAR-20-214, which seeks novel “Research to Improve Native American Health.” These results will inform a subsequent clinical research trial to evaluate the clinical impact and cost-effectiveness for conducti...