Objective: Identification of the most relevant factors leading to severe and persistent Post-Traumatic Stress Disorder (PTSD) presentation in refugee children is critical for prevention and treatment. Using causal inference tools for observational studies, we aimed to estimate the total putative causal effects of the most relevant factors for persistent and severe PTSD in Syrian refugee children living in Informal Tented Settlements (ITS) in Lebanon.Methods: A population-based prospective cohort study of Syrian refugee families living in ITS in Lebanon (BIOPATH study) was analysed. Families with children aged 8-16 years that had left Syria less than 4 years prior to recruitment were included. The first wave was conducted between October 2017 and January 2018. Follow-up data collection was conducted one year later (51.55 +/- 1.84 weeks). A subsample of 134 children was assessed with a structured clinical interview six months after the follow-up (27.02 +/- 7.16 weeks), between December 2018 and August 2019. Of the 2282 families approached in 77 selected settlements, 1600 (70.1%) agreed to participate. After one year, 1438 families were approached and data collected from 1009 families (62.8% re-participation rate). Data from 9 families were excluded during data cleaning. Ninety-eight variables across multiple domains (demographic, psychological, familial and community level) were measured using validated questionnaires and considered for a systematic causal discovery and inference method. Increased risk for severe and persistent PTSD based on symptom score was the primary outcome of interest. This outcome was validated a posteriori through structured clinical interviews in a subsample. Results: 1591 child-caregiver dyads were included (age = 11.44 +/- 2.44 years, 52.6% female) and 16.2% of children were at classified as at risk for severe and persistent PTSD (DSM-5 confirmed diagnoses in clinical interviews 6 months later 62.5% vs 34.5% in children with lower risk, p<.05; clinical severity score 4.5 vs 3.4, p<.01). In the systematic causal discovery and inference analysis, the level of war exposure (OR: 1.07, 95% CI: 1.03-1.11 , p<.01), peer violence victimisation (OR: 1.05 , 95% CI: 1.02-1.08, p<.05), neglect (OR: 1.11 , 95% CI: 1.05-1.17 , p<.01), maltreatment (OR: 1.04 , 95% CI: 1.02-1.07 , p<.05) and caregiver depression (OR: 1.04 , 95% CI: 1.01-1.17 , p<.05) predicted risk for persistent and severe PTSD. The quality of the concurrent refugee environment (OR: 0.55, 95% CI: 0.38-0.77, p<.01) was strongly negatively associated with severe and persistent PTSD presentations.Conclusion: Minimising violent re-victimization and exposure to daily stressors, and addressing caregiver mental health, might prevent the development of severe PTSD in refugee children.