Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated colorectal cancer tumors, however, its relationship with treatment response remains to be explored. Here, the authors suggest that ARID1A mutations may confer intrinsic and acquired resistance to cetuximab treatment. Alterations in genes involved in EGFR/MAPK signaling play an important role in primary (intrinsic) and secondary (acquired) resistance to anti-EGFR therapy in RAS/BRAF wild-type (WT) patients as well as combination therapy with BRAF inhibitors in BRAFV600E patients3. Known mechanisms of resistance to anti-EGFR frequently include upstream mutations in the extracellular domain of EGFR that directly confer resistance to antibody blockade4 and also EGFR downstream signaling reactivation mainly through KRAS, NRAS, and BRAF, activating mutations7, collectively referred to here as extended RAS (eRAS)/BRAF mutations. Additionally, less frequent genetic mechanisms of resistance to cetuximab likely through sustained ERK signaling have been identified, including MAP2K110 and NF112 mutations and KRAS, MET, and ERBB2 amplification15 among others. Yet, for a number of additional patients, resistance is readily observed but the underlying mechanisms driving it have remained poorly defined.Advances in the treatment of metastatic colorectal cancer (mCRC) with targeted therapies, including anti-EGFR  and anti-VEGF  therapy in combination with chemotherapy, have improved the outcome for CRC patientsBy leveraging the genomic biomarker data collected from consenting patients who participated in the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial and other relevant CRC datasets, here we investigate additional mechanisms of resistance to anti-EGFR and anti-VEGF containing therapies. In this work, we show data to support ARID1A mutations confer resistance to cetuximab treatment in colorectal cancer.n = 354), during treatment , and/or at progression or end of the protocol treatment  from CALGB/SWOG 80405, a randomized phase III trial in first-line colorectal cancer patients evaluating the efficacy of chemotherapy plus bevacizumab vs chemotherapy plus cetuximab treatment. For this study and text clarity, bevacizumab and cetuximab will refer to bevacizumab + chemotherapy and cetuximab + chemotherapy, respectively. Chemotherapy was a patient/physician choice of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI). The prevalence of mutations detected in the genes measured in cfDNA of bevacizumab- vs. cetuximab-treated patients was similar between both arms at each of the 3 time points evaluated  from available longitudinal plasma samples collected at baseline  = 0.14, 95% confidence interval (CI) , ARID1A adj. p = 0.02, OR = 0.09, 95% CI , two-tailed Fisher’s exact test  from baseline to end of study for 333 patients with samples at both time points. Relative MAF was calculated as the allele frequency of a given mutation relative the highest reported MAF, and was used to account for the variation in the fraction of tumor vs. normal cell DNA in circulation. Non-synonymous single-nucleotide variants (SNVs) with an increase in relative MAF exceeding 25 percent were considered as mutations likely selected during the course of treatment. Of the 18 genes with at least 2 selected mutations detected in either treatment arm  had a mutation that was already detected (at a lower MAF) at baseline  and the other first detected on treatment (ARID1A Q309*). In contrast, the only bevacizumab-treated patient (SAAAKR) with a selected ARID1A mutation had an ARID1A exon 7 Q758fs, exon 20 G2069fs, and exon 20 I907fs alteration detected at baseline with only the ARID1A exon 20, G2069fs detected at higher MAF at progression  or microsatellite instability-low (MSI-L) tumors23. Intriguingly, we observed 4/6 cetuximab-treated patients with acquired ARID1A mutations were initially diagnosed with left-sided tumors, with all 4 being MSS  and right-sided tumorsMSS Fig. , suggestTaken together, these data indicate that KRAS and ARID1A mutations are enriched in patients treated with cetuximab but not bevacizumab, suggesting ARID1A mutations may also confer resistance to anti-EGFR therapy in 1 L mCRC patients treated with cetuximab.24. We first corroborated that the biomarker evaluable population (BEP) is comparable to the intention to treat (ITT) population in terms of known baseline characteristics and outcome  had known or likely pathogenic ARID1A alterations. This prevalence is consistent with the ~10% prevalence from previous reports of ARID1A mutation prevalence in mCRC26. ARID1A-mutant patients exhibited shorter OS when treated with cetuximab relative to bevacizumab  with the difference being observed in a multivariable model with adjustment for established clinical variables, PCR-based eRAS/BRAF mutation status, and chemo protocol (FOLFOX vs. FOLFIRI) (see methods) for OS  3.3, 95% confidence interval (CI) [1.6–6.8]) and for PFS . In contrast, no difference was observed in OS and PFS for ARID1A-WT patients treated with cetuximab relative to bevacizumab .To further investigate the potential relevance of ARID1A mutations to the resistance to anti-EGFR therapies, we evaluated the association between pretreatment (intrinsic) ARID1A mutational status and outcome in cetuximab- vs. bevacizumab-treated patients. Available archival tissue from 562 participants of the CALGB/SWOG 80405 study were profiled with the FoundationOne® targeted assay29. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). For consistency with CALBG80405, we defined anti-EGFR patients as those who received cetuximab or panitumumab but no bevacizumab at 1 L  vs. bevacizumab-treated patients as those who received bevacizumab without any anti-EGFR at 1 L. By looking at the effect of ARID1A mutation status on the unadjusted OS estimates of eRAS/BRAF WT patients, we found ARID1A mutants have a median OS of 16 months when treated with cetuximab or panitumumab relative to 41 months when treated with bevacizumab , the main effect of ARID1A mutation status on anti-EGFR treatment group was significant. The forest plot confirms the worse outcome for patients without any of known KRAS, NRAS, or BRAF mutation but with ARID1A mutant patients compared to ARID1A WT on cetuximab or panitumumab when controlling for confounding factors, including age, gender, and MSI/MSS status . Patients with ARID1A mutant-like tumors were also less likely to respond  than patients with WT-like tumors when treated with cetuximab, and the proportion of overall confirmed best response rate (ORR) was significantly lower in the ARID1A mutant-like vs. WT-like group . These data are consistent with the concept that the ARID1A mutant-like signature predicts resistance to cetuximab but not bevacizumab.After having identified a signature that captures defects in the SWI/SNF complex, we sought to assess the predictive value of this signature for response to cetuximab compared to bevacizumab. Since eRAS/BRAF-mutant patients are expected to respond poorly to cetuximab37. Since ARID1A genetic or mutation status was not available, we assigned an ARID1A mutant-like signature score to each PDX tumor, and stratified the 132 eRAS/BRAF WT tumors into an ARID1A mutant-like vs. WT-like group based on the top quartile as previously described in Supplementary Fig. p < 0.01, Fig. p = 0.05, ORR = 11% vs. 36%, respectively, Fig. p < 0.001, Fig. p < 0.0001, ORR = 2% vs. 28%, respectively, Fig. We further evaluated the ability of the ARID1A-mutant-like signature to predict decreased sensitivity to anti-EGFR treatment in an independent cohort of 244 cetuximab-treated patient-derived xenografts (PDX) with available response and gene expression data38 with targeted DNA sequencing data on 16,931 CRC tumors to identify other mutations that are either mutually exclusive or co-occurring with ARID1A mutations. We applied the SELECT algorithm32 to all reported mutations and copy-number alterations with known or likely oncogenic significance, and we adjusted for MSI status to remove its effect on the prevalence of detected alterations. Since EGFR is infrequently mutated in treatment-naïve CRC (0.5%)25, we also performed this analysis in the 29,757 FoundationCORE® lung cancer samples, a tumor type where EGFR and ARID1A mutations are more frequently detected at baseline39.To gain further pathway and functional insight into possible genetic interactions underlying ARID1A deficiency-driven resistance to anti-EGFR therapy, we next searched for oncogenic dependencies or mutual exclusivities between ARID1A mutations and other alterations in cancer. We utilized the FoundationCORE® database41. The SELECT algorithm revealed 23 genes in CRC and/or lung with alterations that were significantly mutually exclusive or co-occurring with ARID1A mutation  was the top mutually exclusive alteration with ARID1A mutations in lung cancers  had both SVs . Furthermore, we also observed significant mutually exclusivity between EGFR amplification and ARID1A mutations in lung  and a tendency for mutually exclusivity between ARID1A mutations and EGFR amplification (0.92%) in CRC . Other co-occurring and mutually exclusive signaling pathway genes in CRC included BRAF, KRAS, SMAD4, AMER1, MEN1, and TERT 3, and less frequently alterations in NRAS, BRAF, MEK1, and NF142 in addition to other lower prevalence alterations.In CRC, baseline pre-existing KRAS mutations provide intrinsic resistance to anti-EGFR containing therapies17 and are not likely to be founding clonal events4. We also did not identify mutations preferentially enriched in the bevacizumab-treated patients. The limited number of genes covered on the mutational panel coupled with the bias toward actionable pan-cancer targets may also have limited our ability to discover novel bevacizumab resistance mutations.In this study, by analyzing cfDNA at baseline and end of treatment from the CALGB/SWOG 80405 study, we found that KRAS and ARID1A mutations were positively selected in a subset of the patients treated with cetuximab- but not bevacizumab-containing regimens. These observations may be explained by: (i) evaluation of a broader set of actionable mutations including ARID1A beyond canonical alterations downstream of EGFR such as KRAS/BRAF/NRAS/PI3K, (ii) the large number of patient samples analyzed to detect a low prevalent acquired mechanism of resistance such as ARID1A, and (iii) the ability to compare with a control arm (CALGB/SWOG 80405 was a randomized study). The reasons for not detecting other known prevalent emerging mutations such as EGFR (ECD) in this study are unclear, but could be related to the relative limited genomic heterogeneity and tumor burden in first-line (this study) compared to later lines of treatment as EGFR ECD mutations are thought to take typically longer than KRAS mutations to emergeIntrinsic ARID1A mutations are typically seen in right-sided CRC tumors and associated with MSI-H status and BRAF mutations. In contrast, the acquired ARID1A mutations detected in this study were mainly from patients with left-sided (4/6), MSS (5/6) primary tumors, and were not associated with BRAF alterations (6/6). This “unexpected” high proportion of left-sided ARID1A secondary mutations is consistent with the known increased efficacy (and stronger selective pressure) of EGFR blockade in left-sided tumors . Finally, we did not observe co-occurrence of ARID1A cetuximab-selected mutations with KRAS or other alterations known to cause resistance to cetuximab treatment. Hence, progression on cetuximab in patients with a selected ARID1A mutation is unlikely to be attributed to co-mutation in other known resistance mechanisms, and thus ARID1A selected mutations may independently contribute to resistance to anti-EGFR therapy.43 and is frequently altered in CRC, non-small cell lung cancer (NSCLC), clear cell ovarian cancer, hepatocellular carcinoma, and endometrial cancer among other tumor types49. ARID1A mutations have been previously implicated in tumor progression, chemoresistance, metastatic spread and activation of oncogenic signaling pathways such as PI3K and MAPK. The vast majority of mutations in ARID1A are truncating mutations50, which are thought to promote cancer by destabilizing the SWI/SNF complex to facilitate cell growth51. Since the SWI/SNF complex modulates DNA accessibility for cellular processes involved in chromatin structure including transcription, DNA replication and repair, loss of ARID1A is thought to globally deregulate and impact gene transcription53. The specific molecular mechanisms by which ARID1A mutations contribute to cancer are likely to be complex and remain an area of active investigation. In this context, the emergence of ARID1A mutations in cetuximab-treated patients indicates a previously unsuspected functional link between EGFR signaling and ARID1A/SWI/SNF effectors in CRC patients. Although the biological convergence between these two pathways is not necessarily evident a priori, a recent functional genetic screen in a NSCLC cell line identified loss of function ARID1A and other SWI/SNF components as important mechanisms of resistance to EGFR inhibition in vitro54. Our paper shows that this mechanism of resistance mediated by ARID1A/SWI/SNF loss that was initially uncovered by functional genetic screens in vitro is likely to be relevant in human patients treated with agents that inhibit EGFR signaling.ARID1A is the most frequently mutated subunit of the SWI/SNF chromatin remodeling complex in cancer55, this finding, if validated in a prospective study, may have important clinical implications. Our data suggest that ARID1A mutant patients could be potentially excluded from cetuximab treatment. However, ARID1A mutation by itself may be an imperfect biomarker, as ARID1A downstream function can be impaired by other mechanisms besides mutation.If secondary ARID1A mutations are indeed a mechanism of acquired resistance to cetuximab then intrinsic mutations in this gene may also predict primary resistance to anti-EGFR treatment. By performing correlative analysis between ARID1A status at diagnosis in tissue and outcome in CALGB/SWOG 80405 we were able to show that patients with known or likely intrinsic mutations in ARID1A have indeed worse overall survival on cetuximab (independently of MSI or eRAS/BRAF status) than bevacizumab while this differential outcome was not observed in ARID1A WT patients. We confirmed these observations using real-world data. One possible limitation for this interpretation is that, given its low prevalence in CRC, the number of ARID1A mutants included in these correlative analyses is relatively small. Together these findings suggest that both primary and secondary ARID1A mutations can compensate for the lack of EGFR signaling. Although the prevalence of ARID1A in CRC is relatively low (~5–11%)In an attempt to more broadly characterize these downstream biological consequences at the transcriptional level, we leveraged genomic and gene expression data to discover and validate an ARID1A loss of function-like gene expression signature that not only identifies ARID1A mutant tumors but also more broadly other tumors with likely impairment of the SWI/SNF complex. By applying this signature, we found that ARID1A mutant-like tumors were less responsive to anti-EGFR treatment than the ARID1A WT-like group in CALGB/SWOG 80405. This was also confirmed in eRAS/BRAF WT PDX tumors. Thus, the downstream biological consequences of ARID1A loss of function can also be defined at the phenotypic/transcriptional level. Our data suggest that CRC tumors with functional impairment of ARID1A function (as defined by the ARID1A signature) may also be resistant to anti-EGFR therapies, thus indicating that the prevalence of this phenotype may be broader than what ARID1A genomic mutation data would suggest.58. However, the role of the EGFR pathway in the context of loss of ARID1A/SWI/SNF activity has not been characterized in these studies. The transcriptional convergence between EGFR activation and ARID1A loss provides a likely mechanistic explanation for the contribution of ARID1A mutations to the resistance to anti-EGFR therapy. A detailed molecular characterization of the interaction between these two pathways is beyond the scope of the present manuscript but warrants further investigation.Our data showing that the ARID1A mutant-like signature enriches in transcriptional programs consistent with active EGFR and loss of SWI/SNF activity, suggests that the ARID1A/SWI/SNF complex negatively modulates transcription of EGFR downstream effectors. EGFR signaling is known to promote sensitivity to anti-EGFR therapiesIn CRC patient tumor genomic data, we were able to detect a trend toward a mutually exclusive interaction between ARID1A and rare baseline EGFR amplifications, as well as significant mutually exclusive interactions between ARID1A and BRAF and KRAS, two genes that are downstream of EGFR signaling and known to confer resistance to anti-EGFR therapy. Data from NSCLC patients, in which both EGFR and ARID1A are frequently mutated, confirmed the relevance of this mutually exclusive genetic interaction between these two genes in the context of EGFR dependent tumors. Thus, the mutual exclusive interaction described here provides additional independent confirmation of the relevance of the functional link between ARID1A and EGFR/MAPK-pathway during tumor progression in CRC and NSCLC patients that are EGFR signaling dependent that is consistent with previously published genetic data in NSCLC cell lines.The data presented in this manuscript add to the large and growing body of clinical evidence indicating that most CRCs are addicted, in one way or another, to EGFR/MAPK activation. This is evidenced by the efficacy of cetuximab in WT patients, by the secondary mutations in this pathway emerging in response to anti-EGFR blockade, by the high prevalence of KRAS mutations, and by the sensitivity of BRAF V600E mutations to combinations of cetuximab and BRAFV600E inhibitors. Our results not only indicate that ARID1A could be potentially used, if further confirmed, as a predictive biomarker for excluding patients from cetuximab treatment but also provide a rationale for exploring therapeutic MAPK inhibition in a previously unsuspected genetically defined segment of CRC patients.https://clinicaltrials.gov/ct2/show/NCT00265850, and all participating patients provided written informed consent. Patients were enrolled at centers across the National Cancer Trials Network in the United States and Canada. CALGB is now part of the Alliance for Clinical Trials in Oncology. The study was conducted in accordance with recognized ethical guidelines of the Declaration of Helsinki, CIOMS, Belmont Report, and the U.S. Common Rule. The clinical trial number for this trial is NCT00265850.The presented research complies with all ethical regulations. Institutional review board approval was required at all participating centers, which are listed at 59. Additional information about the study is available at ClinicalTrials.gov identifier: NCT00265850. Best clinical response was determined according to RECIST 1.1 (Sum of the longest diameters of the target lesions on CT scans). The number of patients enrolled in the trial and the blood samples used for analysis are reported in Supplementary Fig. Samples for this analysis were collected from the CALGB/SWOG 80405 trial, which was a phase III trial designed to determine whether the addition of cetuximab compared to bevacizumab to chemotherapies was superior as first-line treatment in advanced or metastatic CRC. The study design, patient eligibility, and clinical outcome of this trial have been reported previouslyThe pathologic diagnosis of each case was confirmed by review of hematoxylin and eosin (H&E) stained slides. Tumors marked by a pathologist based on H&E images were macro-dissected for DNA and RNA extraction. Tumor DNA was extracted by QIAamp DNA formalin-fixed, paraffin-embedded tissue kits . Total RNA was isolated using Roche High Pure FFPE RNA Micro Kit .61. Adaptor-ligated DNA underwent hybrid capture for coding exons of 395 cancer-related genes plus select introns from 31 genes frequently arranged in cancer FoundationOne® panel as previously reported24. In addition, mutation hotspots in AKT, APC, BRAF, CTNNB1, EGFR, FBXW7, HRAS, KRAS, NRAS, PIK3CA, and TP53 were detected by allele-specific PCR from 843 patients, and the detected mutations in those genes have been previously reported23. Unless otherwise indicated, FoundationOne®-based mutations were used. For some analyses, KRAS, NRAS and BRAF hotspot mutations from additional samples were included, as indicated. In addition, comprehensive genomic profiling (CGP) was carried out for 16,931 CRC and 29,757 lung tumors in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory  on all-comers during the course of routine clinical care. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for coding exons from at least 324 cancer-related genes plus select introns from up to 31 genes frequently rearranged in cancer. We assessed all classes of genomic alterations (GA) including short variant (SV), copy-number (CN), and rearrangement alterations62.DNA extracted from 562 patients was submitted to Foundation Medicine  for targeted next-generation sequencing (NGS)-based genomic profiling following standard procedure as previously describedWhole-transcriptome profiles were generated for 578 patients using TruSeq RNA Access technology (Illumina®). RNAseq reads were first aligned to ribosomal RNA sequences to remove ribosomal reads. The remaining reads were aligned to the human reference genome (NCBI Build 38) using GSNAP version “2013-10-10”, allowing maximum of two mismatches per 75 base sequence (parameters: ‘-M 2 -n 10 -B 2 -i 1 -N 1 -w 200000 -E 1–pairmax-rna=200000–clip-overlap). To quantify gene expression levels, the number of reads mapped to the exons of each RefSeq gene was calculated in a strand-specific manner using the functionality provided by the R package GenomicAlignments13 (Bioconductor). RNAseq analysis was performed in R using limma (version 3.53.5) Bioconductor package. Heatmaps were generated with ComplexHeatmap (version 2.13.0) Bioconductor package.g (or in accordance with collection tube manufacturer’s instruction), plasma samples were aliquoted into 1.8 mL cryovials at 0.5 mL per vial, then were processed and frozen within 3 h of collection and stored at −80 °C. For cfDNA analysis, a total of 953 EDTA or citrated plasma specimens (1–2 mL) from the CALGB/SWOG 80405 study collected at different time points  were analyzed using the Guardant 360 cfDNA assay. The Guardant 360 assay is a Clinical Laboratory Improvement Amendments (CLIA)-certified targeted digital sequencing panel designed to detect SNVs, as well as selected insertions/deletions, amplifications, and fusions. cfDNA isolation and sequencing were performed by Guardant Health using previously described methodology65. Briefly, blood was processed upon receipt to isolate plasma by centrifugation at 1600 × g for 10 min at 4 °C. Plasma was immediately aliquoted and stored at −70 °C. Cell-free DNA was extracted from 1 mL aliquots of plasma using the QIAamp circulating nucleic acid kit (Qiagen), concentrated using Agencourt Ampure XP beads (Beckman Coulter), and quantified by Qubit fluorometer . All cfDNA sequencing and analysis was performed at Guardant Health . Illumina sequencing reads were mapped to the hg19/GRCh37 human reference sequence, and genomic alterations in cfDNA were identified from Illumina sequencing data by Guardant Health’s proprietary bioinformatics algorithms. These algorithms quantify the absolute number of unique DNA fragments at a given nucleotide position, thereby enabling circulating tumor DNA to be quantitatively measured as a fraction of total cfDNA.For all patients who enrolled in the CALGB80405 study and consented to have their blood be kept for future unknown use in research to learn about, prevent, treat or cure cancer, one 5 mL citrate tube and three 5 mL EDTA tube were drawn prior to the initiation of protocol therapy (baseline), at first restaging , and at the discontinuation of protocol therapy. After centrifuging for 10 to 15 min at 1300 x 28. Genomic alterations were identified via comprehensive genomic profiling (CGP) of >300 cancer-related genes on FMI’s next-generation sequencing (NGS) test, i.e., FoundationOne® CDx, FoundationOne® or FoundationOne Liquid®62. Our study cohort includes 5511 CRC patients in the disease-specific FH-FMI CGDB who: (a) are in the Q3 2020 release; (b) have a metastatic CRC diagnosis (may be de novo metastatic or have progressed to metastatic disease from early stage CRC diagnosis). The primary endpoint for the Kaplan–Meier Analysis was OS, which is defined as the length of time (in months) from the start of the first-line of therapy (as the index date) until death from any cause or censoring date (we use the end of treatment date). Our analysis was restricted to patients with FMI CGP testing before start of treatment (1 L) for both alteration and WT cohorts. We compared anti-EGFR (cetuximab or panitumumab) treated patients to anti-VEGF therapy (bevacizumab) for patients with ARID1A mutation status available. ARID1A patients with short variant alterations annotated as known and likely were defined as ARID1A mutant positive. For the analysis, Cox proportional hazards (PH) regression models was applied for multivariable analyses to obtain the hazard ratio (HR) and 95% confidence intervals (CIs) while controlling for confounding factors, including age, gender, and MSI status, within the KRAS/NRAS/BRAF (known/likely) WT cohort. Based on the Schoenfeld residuals test results of each comparison group, the PH assumption holds and we do not need to stratify any covariates. KM curves show unadjusted OS with log-rank test used to assess differences between the groups. Multivariate Cox PH models were used to evaluate cetuximab or panitumumab compared to bevacizumab and the interaction with ARID1A status (mutant vs. wildtype) adjusted for confounding factors of age, gender, MSI status, and KRAS/NRAS/BRAF mutation status. We present the forest plot that shows HR (exp(coef) or the instantaneous relative risk) for patients receiving Cetuximab or Panitumumab from the Cox PH models.The data presented in Supplementary Fig. 32. These alterations were curated from the thousands of observed copy-number alterations (CNAs) and somatic mutations observed in the TCGA cohort to enrich for potential driver mutations41. Transcriptional profiles of the 28 ARID1A mutant tumors (with SFE) were compared to the 309 ARID1A-WT tumors  using the limma voom function in R, with eRAS/BRAF status and the interaction between eRAS/BRAF and ARID1A mutation status included as covariates, and genes with and FDR > 0.05 were selected as the mutant-like signature.The ARID1A mutant-like transcriptional signature was derived from the list of differentially expressed genes between ARID1A mutant and WT tumors in TCGA colorectal tumors. To enrich for mutations that would impact the function of the protein, TCGA mutant tumors were defined as those with alterations annotated as selected functional events (SFE) by Mina et al.http://ciriellolab.org/select/select.html32. The ARID1A mutant-like signature score was calculated as the reverse sign of the first principal component of the z-score transformed expression of each gene in the signature. For the PDX cohort, we calculated the ARID1A mutant-like signature score from the gene expression data available at GSE7640258. GEO data was downloaded using the GEOquery (version 2.65.2) Bioconductor package. In both cohorts, tumors were stratified into ARID1A mutant-like and WT-like groups based on quartile . eRAS/BRAF status in the PDX cohort was based on the mutation calls reported for KRAS, BRAF and NRAS58.The ARID1A mutant-like signature comprises the differentially expressed genes between the ARID1A mutant and WT samples with MSI status, eRAS/BRAF status and the interaction between eRAS/BRAF and ARID1A status added as covariates (FDR < 0.05) with the voom function implemented in the limma R package. ARID1A mutation status, MSI and eRAS/BRAF status were all derived from the FMI targeted panel. ARID1A mutation status for TCGA CRC patients was obtained from the Pancan23 genomic alteration matrix of selected functional events available at http://ciriellolab.org/select/select_1.0.tar.gz]. The select algorithm (version 1.0)32 was applied to the known and likely mutation calls from the FMI foundation core database for lung cancer and CRC patients. The hypergeometric test was used to compare the significance of the overlap between the genes identified by SELECT for CRC and lung, and Pathway Commons pathways. Enrichment p-values were corrected for the number of pathways tested using the Benjamini and Hochberg procedure. Complete results from the enrichment analyses are reported in Supplementary Data The SELECT algorithm was used to look for co-occuring and mutually exclusive mutations in FoundationCore database. A copy of the algorithm can be downloaded from the Ciriello lab [KRAS, NRAS, BRAF). All other statistical analysis and figures were generated in Rstudio IDE with R version 4.2.0.The distribution of time-to-event end points was estimated by Kaplan–Meier curves. Associations with OS and PFS were tested using the log-rank test. Pairwise comparisons were corrected for multiple testing using the Benjamini & Hochberg method. A multivariable stratified Cox model was used to identify the association between a biomarker and time-to-event end points. Models were adjusted for age, treatment arm, sex, ECOG score, synchronous vs. metachronous metastases, number of metastatic sites, primary tumor location , MSI status, and eRAS/BRAF , while stratifying for prior adjuvant chemotherapy and prior radiation. For Cox models testing the effect of MSI status on ARID1A-mutant patients OS and PFS, models were adjusted for the clinical variables that were significant in univariable models: age, number of metastatic sites, side, and eRAS/BRAF mutation status (Further information on research design is available in the Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1-4Reporting Summary


Score-Effectiveness framework to identify the built environment factors in the metro catchment area that need to be improved. The study found that the shading facilities, obstacle barriers, and resting seats around pedestrian walkways are the most efficient and imbalanced variables recognized by the crowd. The convenience of overpasses and underpasses are additional efficient imbalance-type variables for leisure and commuting populations, respectively. This indicates that the current level of construction of the above five built environment factors is relatively low, but the construction has a significant impact on the degree of friendliness in supporting pedestrian walkability. In this paper, improvement measures are proposed in a targeted manner in order to achieve the effect of effectively improving the current level of metro catchment area's walkability. The results of the study can provide references to provide strategies for precise pedestrian planning in the metro catchment area, leading to a pedestrian environment with high walking quality.China's metro system is developing rapidly. Walking is the most frequently adopted mode to connect to the metro, the attributes of the pedestrian-built environment around the stations directly influence people's willingness to use the metro. However, few studies have paid attention to the comprehensive assessments of the built environment in the metro catchment area. Thus, this paper attempts to construct a walkability evaluation model that combines subjective and objective perspectives. We collected field data of the built environment factors affecting on walkability in the 800 m buffer zone of eight case metro stations in Dalian city, China. We also collected on-site interviews from 867 passengers to evaluate the walkability. A machine learning-based approach was developed to calculate the weights of walkability variables, followed by constructing a  The metro is featured with safety and punctuality, leading to an advantage of avoiding congestion caused by uncertainty compared to other modes of ground transportation. Thus, an increasing number of travelers choose the metro as their primary mode of transportation. The popularity of the metro has led to a rapid increase in pedestrian flow within the catchment area, which in turn has triggered changes in land values and has had a positive impact on housing prices around the stations . Even thAs the most frequently used mode of transportation, walking usually possesses a higher level of satisfaction compared to public transportation and automobiles . ImproviFurthermore, by taking eight metro stations in Dalian, China as a case study, this study attempts to establish a comprehensive framework for the evaluation of the walking environment of the metro catchment area. The framework combines the subjective environmental perception of pedestrians and the objective environmental accessibility of the metro catchment area. In the framework, a machine learning-based approach is developed to systematically identify the weight of key factors that affect the walkability of metro catchment areas. It is expected that the development framework can provide policymakers and planners with references to form strategy directions for improving the walkability environment of metro catchment areas.The remainder of this paper is organized as follows. Section Literature review presents the review work on the concept of walkability, followed by an overview of influencing factors of walkability, methods of walkability evaluation, and walkability in the metro catchment areas; Section Data introduces the study area, data collection, and description; Section Methodology describes the idea of evaluating the walkability of metro catchment areas, including the introduction of a new method of machine learning; Section Results explains the statistical and modeling results, followed by Section Discussion which holds the discussion and offers policy and practice implications; Section Conclusion concludes the paper and summarizes research limitations.Walkability refers to the ability of humans to walk , Semantic Differential (SD), Public Life in Public Space (PLPS), Neighborhood Quality of Life Study (NQLS) and Pedestrian Environment Review System (PERS) –46. Amonvia walking by taking into account the attenuation effects due to walking distance, intersection density, and block length , Harbor Square (H-S), South China Square (SC-S), Exhibition Center (E-C), Tsingniwa Bridge (TNW-B), Xi'an Road (XA-R), Friendly Square (F-S), and Zhongshan Square (ZS-S), were selected as the sampled stations. These stations can be divided into several types on the basis of their functions related to land use, including residential-dominated, commercial centers, transportation hubs, and landscape open types .Chinese official Guidelines for Planning and Designing Areas along Urban Railways specify that the rail impact area is the region that is about 500–800 m away from the station, within 15 min walking distance to the station entrance. Therefore, the area within 800 meters radius of the station  is taken as the built environment background area for assessing walkability  objective measurement of the built environment of the metro catchment area and (2) subjective perceptions of the walkability of the metro catchment area. Objective data such as pedestrian paths within the built environment were obtained through web-based big data, street maps, and field observations. The subjective perception data was collected by distributing a questionnaire to respondents and quantifying the results with the help of the five-scale Likert approach. The variables in the questionnaire were selected based on the relevant built environment factors affecting station walkability as mentioned above, with consideration of previously studied sidewalk assessment tools  and sideThe questionnaire and field survey was conducted from August 2021 to March 2022. The field survey was divided into two parts: pre-survey and formal survey. The format, clarity, and wording of the content of the questionnaire were improved through a pre-survey of 30 respondents who randomly distributed the questionnaire. The content of the questionnaire was divided into three parts: basic personal information, travel characteristics, and pedestrian satisfaction with the built environment of the metro catchment area. Personal characteristics included information on gender, age, occupation, monthly income, and home address. The travel characteristics include the purpose of travel, the number of trips per week by metro, and the feeder modes of connecting to metro stations. The final part of the questionnaire collected respondents' subjective satisfaction with the built environment factors of the station area. During the formal research process, the familiarity of the metro catchment area was identified on the spot by asking respondents in advance if they frequently traveled to and from the area by metro. Thus, the questionnaires obtained for this study were representative of respondents who regularly take the metro for various purposes and more than two times per week. The researchers distributed a total of 867 questionnaires in clear weather on weekdays and weekends, respectively, with a valid sample size of 800 and an effective rate of 92.3%, of which 486 questionnaires were collected on weekdays, accounting for 60.8%.According to the statistics of personal attributes in A total of 867 valid questionnaires were generated during the research. Based on the available data collected, this study designs a machine learning-based prediction algorithm to assign weight to the variables. The algorithm consists of two modules: principal component analysis (PCA) and feedforward neural network.Figure 3, the model is stable when it is trained more than 50 epochs. The machine learning-based variable weight prediction algorithm effectively combines the objective and subjective to eliminate the scale effect and assign more objective weight to the variables. Based on the collected data, the correlation between different kinds of variables is explored with the help of PCA, the feedforward neural network is utilized to learn the weights variation of each variable with the guiding of the weights generated by PCA. Compared with the traditional correlation analysis and regression analysis, it effectively enhances the robustness of weight prediction and makes the research results of weights have the obvious advantages of being more objective and having higher credibility.Among them, PCA can effectively reduce the dimensionality of different types of data while maintaining multiple variations in data samples. It helps to eliminate the multicollinearity that destroys the statistical significance of independent variables in the data set, thus making the statistical results more accurate. At the same time, the value relationships among multiple data are explained more clearly by assigning variable weight labels. We use PCA to reduce the training time and avoid overfitting problems. When implementing PCA, our model's input is the original data, PCA transforms the data to a new subspace. Then we feed the output to the feedforward neural network. We designed the feedforward neural network with four fully-connected layers with 29, 128, 64, and 29 nodes in each layer. The feedforward neural network learns the relationship between the input and output manually. We use Adam Optimizer to train the feedforward model because Adam can tune the learning rates automatically. To compare the difference between the prediction and groundtruth. We leverage the MSE loss function. To get a stable neural network model, we train our model for 250 epochs. We can see from The weight of the variable represents the degree of the effect of the pedestrian environment factor on the walkability of the metro catchment area, and some variables even have a critical role. It is reasonable to discover the current problems and directions for improvement in the pedestrian environment by deeply exploring the individual factors that significantly affect the walkability of the metro catchment area. Therefore, this study combines the weighting results with the relevant built environment evaluation scores of the catchment area's current walkability to construct a “Score- Effectiveness” (S-E) two-dimensional quadrant diagram. This framework allows for a comprehensive analysis of the two-way correlation between the walkability performance of each built environment variable in the catchment area and its corresponding weight. This can fully illustrate the correspondence between the current status scores of variables and their effectiveness, to dig out the most sensitive existing problems related to walkability in the catchment area. In particular, for those built environment factors with low scores and high effectiveness, targeted improvement strategies that minimize the cost and maximize the benefit can significantly improve the walkability of the station catchment area. These strategies can precisely and effectively enhance the objective walkability and the subjective pedestrian friendliness of the station catchment area .Due to the difference in the unit of selected data, the variables need to be normalized before entering the algorithm model. The evaluation results of the subjective variables are obtained by averaging the five-scale Likert scores of the eight stations, which ranged between 1 and 5 scores. For the objective variables, the scores vary in magnitude due to the existence of different scales. Therefore, the mean of the objective variables was normalized, followed by transferring into the same interval as the subjective scores, thus eliminating the problem of subjective and objective scales, as follows.Y is the normalized mapped value; yMAX is the maximum value of the mapped target interval; yMIN is the minimum value of the mapped target interval; XMAX is the maximum value in the original dataset; XMIN is the minimum value in the original dataset; Where The scores of each variable are shown in As for the subjective variables, the width of the pedestrian paths in the catchment area, the degree of social security, street lighting facilities, and the neatness of the pedestrian paths were generally recognized by the respondents; the scores of the rest seating facilities, shading facilities and the degree of barrier blockage around the pedestrian paths were significantly lower than the other variables. Combined with the field survey and interviews, most walking paths in the catchment area have problems such as a lack of service facilities, space encroachment, and unclear management.For the designed algorithm, the PCA is used to calculate the weights of each variable based on the collected data, the output of the weight calculated by the PCA is used as the data labels, and the feedforward neural network is used to learn the robust mapping from the variable samples to the weight labels. The loss function of this feedforward neural network gradually decreases during the training process until the network converges. The convergence process is shown in The modeling results of variable weights are shown in As a comparison, convenience and safety variables such as a7 (Ease of pedestrian crossing), a8 (Ease of crossing at flyovers), a9 (Ease of crossing at underpasses), a10 (Signage facilities), a11 , a12 (Street lighting facilities), a13 (Degree of traffic safety) and a14  have weights above 0.05, indicating the important role on affecting the walkability of metro areas. Among these convenience and safety factors, metro users may have many concerns about social security (a14 with the highest weight of 0.062) when connecting the metro transit.Regarding the comfort and pleasure variables, only a15  and a20 (Open space density) have weights below 0.01, while the remaining factors have significantly greater weights than the previous two, including a16 , a17 (Sheltering facilities), a18 (Degree of obstruction), a19 , a21 (Public artwork), a22 , a23 (Degree of greenery and landscape), and a24 (Degree of pedestrian congestion). Within the comfort and pleasantness variables, people may place more importance on the cleanliness of the walkway (a12 with the highest weight of 0.058).On the contrary, most of the variables in diversity have weights below 0.01, such as a25 (Density of living facilities), a26 , a27 , and a28 (Density of transportation facilities). And the weight of a29  is higher than 0.05, which is five times more than the weight values of other variables in the diversity. This indicates that metro users may care more about the façade form of buildings on both sides of the walkway than the density of various service facilities in the catchment area.Score- Effectiveness” fit quadrant in which the horizontal coordinates are the weights obtained from the variable weight prediction algorithm and the vertical coordinates are the scores of the current variables. The baseline of the four quadrants is the mean value of the weights and satisfaction scores as the parallel axes of the horizontal and vertical coordinates, respectively. To form an effective, precise, and efficient optimization strategy based on field surveys and research.In this study, we construct a framework of the “As shown in By counting the data from the questionnaire, as shown in In this study, both subjective and objective perspectives are applied to evaluate the walkability of the metro catchment area. An approach of predicting the weight of variables based on machine learning technique is developed to accurately measure the importance of built environment factors that affect walkability. Among the selected built environment factors, the shade facilities, obstacle barriers, and resting seats around the pedestrian paths were found to be highly effective and imbalanced variables recognized as fixed by the population. indicating the necessity for improvement. Meanwhile, the ease of crossing the flyovers and underpasses are additional efficient imbalance-type variables for the leisure and commuting populations. On the basis of the analysis in terms of the five efficient imbalance-type variables, this paper proposes targeted optimization strategies accordingly.First, pedestrian bridges, an important measure to improve the convenience of walking, are suggested to be installed at traffic nodes such as main roads with high traffic flow and large safety hazards. In Dalian city, motorways, tramways, sidewalks, etc. are crisscrossed in the metro catchment area, causing major hidden dangers to the convenience and safety of pedestrians crossing the street. However, our field observation found that overpass crossing facilities in Dalian are extremely absent, which makes walkers inconvenient for crossing the road. Therefore, overpass crossing facilities should be added at appropriate locations around the catchment area to enhance walkability and form a friendly walking space to separate pedestrians and vehicles . In addiSecond, during the interviews, most of the interviewees reported that the interior of the underpass was too dark, poorly tidied, and had a low level of security. It is recommended that large glass areas be used at the entrances and exits of underground passages to introduce a greater range of natural light. Strengthen the relevant management personnel to improve efforts, pay attention to health cleaning, post-maintenance and social security. Reduce the situation of mobile vendors occupying underground traffic sex paths and adopt time-sharing and centralized management. In addition, the underground passageway of the metro catchment area can and should be combined with the surrounding underground commercial space to maximize the use of the pedestrian flow and vitality brought by the station. The benefits are maximized while reducing the pressure of pedestrian flow in the ground commercial walkway.Third, it is suggested to appropriately improve the ability of the shading facilities to cope with extreme weather. Possible measures include planting street trees along the avenues, building eaves, and setting corridors and canopies. According to the field study, there are very few sheltering facilities along the route to the metro stations, which makes metro users uncomfortable walking to the stations in bad weather. It is suggested to use some flexible sheltering facilities, such as folding devices similar to umbrellas on both sides of the walkway. In addition, shelter facilities can be also designed by integrating the functions of greening and rainwater collection collectively. These techniques will not only improve the overall environmental quality but also makes resources to be utilized more effectively.Fourth, enhancing the environmental management and optimization in the metro catchment area is encouraged. The field survey also found that the pedestrian space in the catchment area is seriously encroached upon by commercial and advertising obstacles. Excessive space encroachment can directly lead to a significant reduction in walkability because of the increasing traffic chaos and safety risk. Therefore, it is recommended that the relevant authorities should develop management measures to prohibit commercial and advertising barriers in the pedestrian space, particularly around the entrance of metro stations where passengers are usually crowded, to reduce its negative impact on walkability.Finally, the metro catchment area should be provided with public seating and resting space approximately. In this study, we found that resting seating facilities along the walkway have a positive impact on station area walkability, which is in line with the results of previous studies , 82. DalCurrently, the urban metro system in China is developing rapidly. However, the development of the metro catchment areas, particularly the planning and management of walking-related facilities, does not meet well with demands  of metro passengers. Considering that the land use has been planned, the optimization of the built environment of the metro catchment area is easier to implement and more effective than the reorganization of built environment factors. In this paper, subjective and objective variables of metro catchment area walkability are effectively combined. Through the innovative machine learning-based variable weight prediction algorithm, the weight value of each variable is obtained more scientifically and objectively. Based on this, this study further constructs a “Score-Effectiveness” suitability system to precisely identify the built environment factors that should be improved to enhance walkability in metro catchment areas.The results of the study help to understand the priorities of built environment factors that affect the walkability of metro catchment areas, as well as to pinpoint the existing problems related to the walking connection to metro stations. A comparative analysis of the stratification of the population was conducted to find out the differentiated demand for metro catchment area walkability by populations who travel for both commuting and leisure purposes. This study provides relevant governments and planners with targeted and effective optimization strategies to make the metro areas more walkable. The major contributions of this study include: (1) to construct the “Score-Effectiveness” framework to identify the imbalanced factors in terms of the built environment, and hence, contribute to providing targeted policies to improve the walkability of metro areas; (2) to collectively identify the weight of objective and subjective built environment factors through developing a machine learning-based approach, which makes it possible to compare the importance of objective and subjective built environment factors.However, there are limitations to this study. First, due to the difficulties in data collection, some built environment variables such as traffic congestion, noise, and air pollution  that mayThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.WX and YG: conceptualization. PZ and YG: funding acquisition, validation, and writing—review and editing. WX: formal analysis, supervision, methodology, and writing—original draft. BL and LS: investigation. MX: machine learning algorithm design and practice. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation of China (No. 51978447) and the Major Training Project of Team+Project in Tianjin (No. XC202061).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A central kitchen model for implementing a school feeding program in the Philippines increased demand for local health interventions, empowered civil society, and held local governments accountable for multisectoral action in a decentralized government. Combining the logistics of a centralized in-school program with decentralized implementation to improve the diets and nutritional status of school-age children, a community-supported central kitchen model prepared and packed meals for schools.The model’s success was attributed to financial sustainability institutionalized at the national level through laws, operational sustainability maintained by local government units (LGUs), strong community support, mobilization from volunteers, and embedding of the program in the city’s and municipalities’ social networks.Community involvement in central kitchen operations translated into volunteer accountability and program ownership that organized local interests and enabled community members to demand related health, education, and social services from their local elected officials, contributing to their sustained interest in participating in the program.In decentralized settings, national health agendas and services can successfully be devolved to LGUs when they are afforded decision-making space to adapt programs according to local needs and resources with national support.When developing health interventions, nongovernmental organizations should consider factors influencing program sustainability such as the involvement of multisectoral community-led action from inception and the country’s government structure. In devolved governments like the Philippines, local government units (LGUs) must be engaged to develop and coordinate responses to tackle the multisectoral problem of childhood undernutrition. However, current Philippine nutrition interventions, such as decentralized school feeding programs (SFPs), generally rely on the national government, public school teachers, or the private sector for implementation, with mixed results. The central kitchen model for SFPs was developed by 2 Philippine nongovernmental organizations and facilitated large-scale in-school feeding through community multisectoral action. This case study documented coordination processes in February 2018 for 1 urban city and 1 rural province—the model’s earliest large-scale implementation sites—that contributed to its institutionalization and sustainability. Data from 24-hour dietary recalls with 308 rural and 310 urban public school students and household surveys with their caregivers showed undernutrition was an urgent problem. Enabling factors and innovative local solutions were explored in focus group discussions with 160 multisector participants and implementers in health care, education, and government, as well as volunteers, parents, and central kitchen staff. The locally led and operated central kitchens promoted community ownership by embedding volunteer pools in social networks and spurring demand for related social services from their LGU. With the LGU as the face of implementation, operations were sustained despite political leadership changes, fostering local government stewardship over nutrition. Leveraging national legislation and funding for SFPs and guided by the Department of Education’s standards for SFP eligibility, LGUs had room to adapt the model to local needs. Central kitchens afforded opportunities for scale-up and flexibility that were utilized during natural disasters and the coronavirus disease (COVID-19) pandemic. The case demonstrated empowering civil society can hold volunteers, local implementers, and local governments accountable for multisectoral action in decentralized settings. The model may serve as a template for how other social services can be scaled and implemented in devolved settings. Childhood malnutrition is an immediate, lifetime, and intergenerational concern. Undernutrition increases risk of diseases,The Philippines is a lower-middle-income country in Southeast Asia,To address the problem of malnutrition, in 2018, the Philippines ratified Republic Act 11037, referred to as the National Feeding Program (NFP) Law, which institutionalized an NFP for undernourished children aged 3–5 years in public day care programs and a school-based feeding program (SFP) for children in kindergarten through grade 6 in public schools.The NFP provides at least 1 fortified meal to undernourished children in public schools and day care centers over a minimum period of 120 days. Meals include components with micronutrient supplementation such as fortified milk and iodized salt. Children are deemed undernourished if they fall below the World Health Organization (WHO) Child Growth Standards (CGS) for wasting (body-mass-index [BMI]-for-age below -2 Z-score line).–,However, there remains a lack of consensus on the impact of these SFPs. While literature acknowledges enhancement in caloric and micronutrient intake, these changes do not always correspond to anthropometric improvements.,The modality of implementation affects outcomes as well. Based on service delivery, SFPs are broadly classified into 2 groups: (1) in-school feeding, when children eat the meals in school; or (2) take-home rations, when families are given food for children attending school regularly.–Another service delivery classification is based on the program’s back-end structure. In the traditional centralized model, a government or nonprofit organization distributes food to schools. In contrast, the decentralized model, or “home-grown school meals,” devolves the procurement and operations to schools that purchase food locally from farmers.–For decades, decentralized, in-school feeding programs have been implemented by DepEd, private organizations, and nongovernmental organizations (NGOs) in the Philippines with mixed results. Previous evaluations found operational issues, such as the quality of meals and measuring equipment, human resource shortages, and household characteristics, contributed to students’ regression and program unsustainability and stressed the need for alternative interventions and innovations to traditional feeding models.–The central kitchen model we describe in this study is an innovation of SFPs that blends the streamlined logistics of a centralized SFP with the community-building benefits of a decentralized SFP.The NFP is a school-based feeding program that provides at least 1 fortified meal to undernourished children in public school and day care centers.The central kitchen model blends the streamlined logistics of a centralized SFP with the community-building benefits of a decentralized SFP to facilitate large-scale feeding.,–Local support for these programs is critical in the Philippines, where the government is decentralized and the national agenda for health and nutrition is operationalized by local government units (LGUs).This study presents 2 such LGUs, 1 urban and 1 rural, where the adoption of a locally developed central kitchen model for SFPs has withstood shocks and changes in political leadership and improved children’s health and communities' civic engagement outcomes. We examine the common challenges faced by implementers and key factors that contributed to the program’s success and sustainability, which could inform NFP Law implementation and may be applied to other community-based multisector inventions.Busog, Lusog, Talino feeding program, where parent volunteers prepared meals for undernourished children. ACED also learned from Akshaya Patra Foundation’s Mid-day Meal Program for underserved public school students in India, which established central kitchens to cook meals and deliver them to several schools in the area.In 2011, the Ateneo Center for Educational Development (ACED), an education NGO, developed a template for Blueplate for Better Learning, a large-scale feeding program for public elementary school students. The template was inspired by a partnership with Jollibee Foundation’s To adapt it to the Philippine context, which has a devolved form of government,Process innovations in preparing and packaging food enabled cost-effective and replicable scale-up of central kitchens to provide food for entire cities or municipalities. In central kitchens, standardized food preparation and packing took place to maximize resources and avoid waste. This innovation sought to alleviate the burden of traditional SFPs on teachers, who procured ingredients, cooked, fed, and cleaned up after students, all of which detracted focus from teaching. Though DepEd models envisioned parent volunteers fulfilling these roles, volunteerism was often inconsistent or unsustainable.ACED’s central kitchen model focused on community empowerment through community ownership, with local volunteers integral to central kitchen and feeding activities.The central kitchen model innovated upon these programs in the following 3 ways.Central kitchens enable standardized, cost-effective food preparation and packaging to maximize resources and avoid waste.In 2014, Gawad Kalinga, a community development foundation, partnered with ACED to expand the use of the model across the country, culminating with central kitchens as the main modality of SFPs in the NFP Law .Initially, ACED and GK partnered with willing LGUs for 1-year pilots. The 2 NGOs provided training and technology, as well as building a back-end support infrastructure such as procurement, liquidation, and monitoring systems. They also helped orient teachers and kitchen staff for operations. After the pilot, LGUs’ were evaluated on their cohesion, leadership, and volunteerism. Though the model has more than 100 central kitchens around the country, many of these remain privately funded and operated. Pilots were deemed successful only in sites where LGUs demonstrated both interest and capability for implementation, where capability was the ability to mobilize the community and secure the buy-in of local stakeholders in a process called “social preparation,” as volunteers sustained kitchen and feeding operations.After the pilot year , the successful LGUs proposed the program to DepEd, which funded the program for subsequent years through their SFP budget . The proThe current roles of each stakeholder are presented in To strengthen the program to scale up nationally, develop an effective and sustainable large-scale comprehensive feeding program that can reach all malnourished children in public elementary schools in the PhilippinesTo provide access to quality foods, change dietary habits, and improve health and education outcomes:To reduce rates of malnutrition, stunting, and wasting among participating childrenTo lay a foundation for lifelong healthy eating based on favorable experiences, the acquisition of sufficient skills, and confidence in one’s capacity to practice a healthy lifestyleTo encourage maximum community support for the feeding program and empower the school community and other stakeholders to take the lead role in the programTo encourage a whole-of-society approach through multisectoral investment to improve the health and well-being of students and their familiesMultisectoral coordination among schools, parents, the community, LGUs, NGAs, and NGOs is crucial to meet the following program objectives.Multisectoral coordination among schools, parents, community, LGUs, and NGOs is crucial to develop an effective and sustainable large-scale comprehensive feeding program.Concrete mechanisms to facilitate coordination were built into the program even before implementation. First, the NGOs consulted with local stakeholders to understand their capabilities and set expectations. Then, central kitchen staff were trained in food preparation, kitchen maintenance, and management, such as inventory, logistics, volunteer management, and preparing reports for monitoring and transparency. A project coordinator from the NGO guided the process during the pilot phase. Project coordinators monitored daily feeding operations and liaised with central kitchen staff, school administrators, and local government. Unlike in the traditional DepEd SFP, feeding coordinators monitored volunteers in schools and compiled feeding and nutrition reports, kitchen staff monitored volunteer attendance and inventory, and LGU staff handled procurement and liquidation reports. All reports were processed by the LGU and sent to DepEd for accountability.During implementation, national leadership through DepEd and local implementation through LGUs allowed operations to run continuously throughout the school year. Leveraging existing policies for school feeding, DepEd set standards for program eligibility, targets for rehabilitation, and funds SFPs. Through their local budgets, LGUs hired feeding coordinators to bridge the oversight role initially filled by ACED and permanent staff within the LGU that were responsible for local nutrition programs’ budget and procurement. The provincial LGU in this study also established an annual Hunger Summit with NGOs, inviting all stakeholders, from DepEd to community members, to be transparent about program performance for the year.At the national level, ACED and GK adopted the Hunger Summit to generate awareness of malnutrition among LCEs and legislators and share best practices from the central kitchen SFP model. This summit led to the incorporation of the LGU-led central kitchen model in DepEd’s SFP operations in 2017 and the NFP Law in 2018.Annually, the NGOs continue to conduct a quality control assessment in all central kitchens. However, because their goal is to transfer monitoring and evaluation to LGUs and DepEd, they developed a web-based data collection and monitoring system and began training project coordinators on its use as a crucial input in LGUs’ and DepEd’s evaluation of SFPs, though this has not yet been completed.Student beneficiaries are identified through the same standards as DepEd’s SFPs. If their BMI-for-age falls below the −2 Z-score line based on the WHO CGS, they are considered wasted and enrolled in the program. At the end of the 130-day feeding cycle, 10 days longer than the standard DepEd SFP, a beneficiary is considered rehabilitated if their BMI-for-age is between the −2 and +2 Z-score lines of the WHO CGS. The program aims to rehabilitate 90% of beneficiaries. Although not originally prescribed by DepEd or the NGOs, a unique feature of the program is that through LGU coordination with the local health office, nonrehabilitated beneficiaries are given health check-ups to determine whether other health factors have contributed to their malnutrition.A unique feature of the program is that through LGU coordination with the local health office, nonrehabilitated beneficiaries are given health check-ups to determine whether other health factors contribute to their malnutrition.For this cross-sectional case study, we employed a mixed-methods approach to examine the Philippine central kitchen model for SFPs. We chose 1 city in Metro Manila and 1 province in Mindanao for the study setting. The province is comprised of 11 municipalities, which include an urban town or city and its surrounding rural areas. In 2012, the urban site of the study became the first city-wide implementation of the program through the city LGU, while the rural site of the study was the first to implement it province-wide in 2016 through the provincial LGU.To provide context for the program setting, elementary school students were randomly sampled from all 41 public schools of the urban site, and 60 of the 352 public schools of the province , using aData collection took place in February 2018 for the city and October 2019 for the province. Nutritionist-enumerators conducted 24-hour dietary recalls 3 times (2 weekdays and 1 weekend) within the week following standard practice to accurately compute their average daily dietary intake.To understand program operations and multisectoral coordination in its implementation, participants from different sectors were recruited for guided focus groups. Focus group discussions (FGDs) with parents, educators, city and provincial local government officials, government employees from local offices of national agencies, health care workers, and central kitchen staff  providedDescriptive statistics from food recalls and household surveys provided context for respondents’ nutritional adequacy and household food security status in both sites. Qualitative thematic analysis on the FGD transcripts aimed to identify trends, agreeing or conflicting ideas, and factors contributing to the successes or shortcomings of the program from multisectoral perspectives.Ethical approval was granted by the Ateneo University Research Ethics Office, and all participants gave their written informed consent. The sites were deidentified to ensure confidentiality of local government officials and school administrators participating in the FGDs, who could be identified by their location.Undernutrition was a pressing issue at both implementation sites. Among the households surveyed, only 9.77% of rural households and 39.03% of urban households were food secure. Based on the Philippine Dietary Reference Intakes,According to a report by ACED for the urban site,The feeding process was similar to those of traditional SFPs.Though these individual-level effects cannot directly be attributed to the central kitchen model, the program has standardized nutritionally balanced meals developed by nutritionists to ensure children they were exposed to a variety of vegetables and age-appropriate meal portions. Under the traditional decentralized SFPs, teachers explained that they were not able to consistently follow DepEd’s recommended recipes due to a lack of available ingredients, fluctuations in market prices, and difficulties in meal preparation on top of their teaching responsibilities.,Based on the program’s secondary goal to improve education outcomes, in the FGDs, a local government official and an educator reported that program participation increased school attendance and participation because students no longer needed to find food before classes or leave campus during lunch hours, especially for rural beneficiaries whose homes were far from school. These findings were similar to previous evaluations of Philippine SFPs, which showed that attendance improved after participation.More pressing was the challenge of regression during the summer months when schools were not in operation. The following sections discuss how the respective communities overcame issues of nutritional regression, volunteer commitment, and operational sustainability.Three interconnected mechanisms facilitated the program’s successful implementation in the 2 sites: community involvement and program ownership, local government stewardship and coordination, and program scale-up and sustainability.Implementation of the SFP necessitated the creation of volunteer networks and grassroots support that increased demand for more community-based health interventions and protected program sustainability from threats of political interference. Community participation and roles varied in the 2 LGUs, as LGUs in the Philippines are given some discretionary funds and administrative capacity under the country’s Local Government Code of 1991 (Republic Act 7160).Rural communities were less dense and geographically dispersed across the large province. Consequently, 10 of the 11 municipalities in the rural site had 1 central kitchen established in contrast to the single central kitchen of the city. The exception was 1 municipality, which required 3 central kitchens because of its size. While kitchen staff were drawn from the community, they were considered government employees and paid a salary, relying less on informal community ties to ensure responsibilities were fulfilled. Nonetheless, community buy-in to the importance of nutrition, which began with the SFP, facilitated local engagement in the program: feeding volunteers were uncompensated but consistently assisted in the schools. Though the program was a provincial-level, then municipal-level initiative, barangay  officials and residents volunteered to deliver meals to their respective schools. Volunteer local government employees also supported a provincial program, which provided aid to nonrehabilitated beneficiaries’ families over the summer break, to mitigate household-level causes of malnutrition.In the urban site, 98% of volunteers were uncompensated, and 66% of volunteers did not have children participating in the SFP. However, the central kitchen could reliably assign 50 volunteers from their pool of about 600 to arrive for the day’s operations. The sustainability of the city’s volunteer pool over 6 years was attributed to ingraining volunteer operations within community relationships. In the initial phases of implementation, SFP volunteers were drawn from local people’s organizations, in particular, women’s groups supporting the LCE. As the program matured, recruitment from civil society groups waned. In 2018, 29% of volunteers joined through people’s organizations, while 51% were recruited through information from friendships and neighborhood relationships. Urban volunteers were recognized for their participation through a year-end party organized by the LGU.Why do you volunteer? You don’t have children in the feeding [program]. —InterviewerBecause in the beginning, the officers at [civil-society association] are my clique, but even if I wasn’t an officer, [they said] “Oh, sis, come on!” So there. Helping out. Until they left already. When someone else was in charge and needed volunteers, you know, experienced ones. “Okay, yeah,” was what I said…so I already got used to helping out. — Parent, urban FGDThe sustainability of the city’s volunteer pool over 8 years was attributed to ingraining volunteer operations within community relationships.Communities’ active participation in local policy encouraged demand for more integrated health services. LGUs responded by subsidizing medical check-ups and treatment for nonrehabilitated beneficiaries, as DepEd found that students whose nutritional status did not improve after the feeding cycle usually had underlying medical concerns, according to health workers in the focus group. LGUs also made structural investments in social services through programs sustained by community volunteerism. SFP kitchens were used in disaster relief operations, as the country is vulnerable to tropical storms. The urban LGU continued feeding operations during summer classes, as the SFP was integrated into an ambitious multifaceted educational investment program including educational reform, parenting seminars, and building physical and technological infrastructure. To generate another source of ingredients for central kitchens, the provincial LGU launched home and school gardening programs for household income generation and food production, and locally sourced ingredients for feeding.People’s roles in the success of their own programs created a sense of ownership that withstood changes in political leadership. Since its pilot in 2011, the city SFP has persisted through 4 terms and 2 mayors, while the provincial SFP has operated since 2016. This culminated in local ordinances that codified local priority and support for the SFP, according to local government officials in focus groups, ensuring these programs’ implementation regardless of who is elected to local office.The program underwent an iterative process of planning, implementation, and evaluation with multisectoral input, which helped overcome challenges faced by traditional feeding models. Public school feeding was originally under the purview of DepEd, and operations were decentralized to individual schools; however, schools faced difficulties coordinating with the centralized NGA. School staff identified beneficiaries, bought and cooked ingredients, and submitted progress reports and liquidation forms for reimbursement. In both urban and rural settings, this additional uncompensated work was assigned to teachers, who reported being unable to focus on teaching and paying out-of-pocket when ingredients were insufficient or unavailable in the market. DepEd’s hierarchical bureaucratic processes delayed reimbursements and incentivized schools to decline feeding programs.Before the [DepEd SFP], I fed [students] through the help of the parents. So, every 3 times a week, we cooked. We got our funds from the [school] canteen…Later, the [DepEd SFP] came. We were given a budget of 15-pesos or 16-pesos per child. So, last year—2 years ago—I think, I was asked if I would accept the SBFP again. I really didn’t want anymore because it was so tiring being the [SBFP] coordinator. Because I was the one who went to the market and I was the one who liquidated, and then if the parents I assigned didn’t come in or come here, I was the one who had to cook. So, it was really tiring, really tiring. —Educator, rural FGDWhen the centralized-kitchen model was first proposed, schools in the city perceived the LGU did not trust them to implement the program on their own, as one local government official reported. The LCE held dialogues with all public school administrators to onboard them. Following the successful pilot, the LGU then coordinated with DepEd to develop a unified work-and-financial plan, as each had unique liquidation and procurement protocols that necessitated a new system to interface between them. Through the LGUs’ efforts, initial ambivalence toward the program was overcome.As another local government official stated, LGUs deliberately engaged other sectors to minimize threats to implementation. Though successful pilots were funded by DepEd in subsequent years of operation, LGUs augmented funds through their internal revenue allotment and contributed to building and renovating kitchens and hiring full-time kitchen staff. By mobilizing their civil society groups, LGUs created an initial pool of volunteers. They also responded to context-specific needs. To alleviate the burden of SFP implementation on teachers, the city LGU hired full-time feeding coordinators to conduct feeding and monitoring activities. The provincial LGU coordinated transportation at the barangay-level so teachers did not need to pick up or return meal containers. LGUs also played an important role in expectation setting and both formal and informal accountability. When some schools tasked feeding coordinators with teaching errands, they were reprimanded by the mayor and the practice was stopped. Volunteers, though unpaid, attend an annual seminar retreat organized by the LGU to refresh their training and raise morale. As such, stakeholders felt recognized and seen and were incentivized to perform better because they were being rewarded or sanctioned for their actions.You see your name has a blank everywhere. Then you feel ashamed moving forward [laughter]. I see my name is blank, I get ashamed to be absent. —Central kitchen volunteer, urban FGDIt’s unacceptable that you don’t find a solution. You need to find a solution because every day there are those [students] who need to eat. —Central kitchen staff, rural FGDLGUs deliberately engaged other sectors to minimize threats to implementation such as burden on teachers to feed and monitor and challenges in transporting meals.Because the LGU sat at the intersection of different government agencies, the central kitchens were maximized across sectors. Coordinating with the DSWD’s city office, the central kitchens also provided universal feeding for the city’s 70 day care centers as an early childhood health intervention. Collaborating with the local health care sector, LGUs began to include micronutrient supplementation in the SFP. When class suspensions occurred, LGUs transported packed meals to shelters, detention centers, and health care workers, to prevent food waste. The LGUs remained receptive to feedback from parents, teachers, and implementation partners. FGD participants often mentioned the modification of the feeding menu for each locale, accounting for local market availability and familiarity with the ingredients used. For instance, tomato-based sauces had small amounts of added sugar or used Filipino-style sweet sauce popular in the country. In the rural site, higher energy requirements necessitated increasing rice portions. Given the limited availability of vegetables, local vegetables were used, and potatoes were substituted with sweet potatoes. Instead of mushroom sauce, the province used coconut milk with turmeric.Students and parents initially complained about every meal being soup-based with finely chopped viands. Though research-based and nutritious, when packed with rice, the meals would resemble slop or porridge. Drier viands were quickly substituted, increasing the acceptability of the program.They [students] compare the food with what was there before. “At least the one before, our viands were delicious.” You could really see the viand, the beef and the contents…Because now, we chop [everything], ground beef. —Educator, rural FGDBefore it was like that, there were really those [meals] that the children didn’t want to eat, especially the food that was sweet, the one like the food of the elderly. —Parent, urban FGDVisible successes in multisectoral collaboration have fostered a culture of data sharing and evidence-based decision making among stakeholders. Respondents from all sectors proudly shared that their SFP protocols were based on research, making them trustworthy. Program data were not only collected from schools but also compared to program goals. Results and recommendations were presented to school principals, feeding coordinators, and kitchen managers semiannually by the LGU and NGOs.It’s not really an issue for us because of support. All the programs and projects of the LGU, we always support…Because we know that those are beneficial to us, to the children, to the community, to the parents. Just like another project they have that’s also ongoing, the [parent-teacher seminars]. We support the LGU because we know the results of it will benefit us too…Why not support, right? —Educator, urban FGDActually, Mayor looked forward to the [evaluation] study. Because we wanted [to know] how can we improve the feeding more. Because the problem of malnutrition does not originate from just a simple problem, right? —Local government employee, urban FGDMultisectoral involvement in the SFP had spurred investments in physical and social infrastructure that allowed the program to continue operations despite crises. Despite the shift to remote learning during the COVID-19 pandemic, central kitchen operations continued. In the provincial site, meals were delivered to barangays and distributed directly to households by barangay health workers, barangay nutrition scholars, and volunteers from the Sanggunian ng Kabataan (barangay youth councils).In the city, the central kitchen provided meals to health care workers at the height of community lockdowns from March to May 2020, when mobility was limited to reduce the spread of COVID-19. Due to limitations on gathering sizes and community quarantines, central kitchen operations were reduced. Through the central kitchen channels, beneficiary children were initially given food packs and Nutribun, fortified bread distributed in DepEd’s usual SFP. However, full kitchen operations are planned to resume in November 2022 as all students in the country return to on-site classes.The central kitchen model eased the scaling-up process by facilitating LGU initiatives to implement universal feeding in economically disadvantaged areas, such as a relocated community in the city, and geographically isolated and disadvantaged areas in the province. This was enabled in part by economies of scale.The central kitchen model eased the scaling up process by facilitating LGU initiatives to implement universal feeding in economically disadvantaged areas and geographically isolated and disadvantaged areas in the province.The success of the central kitchen SFP model has prompted other localities to inquire about the program template for implementation in their own LGUs.Our visitors—they also benchmark against us—love shortcuts. Because immediately they want the root. “Where’s the root?” …They’re looking for the root of the problem. Why is it like that? Because in their [operations], there are volunteers, but it still failed. — Central kitchen staff, urban FGDIn addition to the assistance from volunteers, a key contributor to success was the input received from multiple stakeholders, which led to improvements in existing feeding procedures as well as innovations applicable to other local government programs. For instance, implementers expressed a major concern about the need for a single database for feeding coordinators, principals, DepEd, ACED, and GK, with each having different levels of access to the data while maintaining children’s data privacy. This prompted ACED’s development of a web-based integrated nutrition database where schools input individuals’ nutrition data, DepEd’s local offices consolidate them, LGUs generate reports, and ACED provides recommendations for LGU interventions beyond SFP. User training for the application was conducted in 2019; the full pilot scheduled for 2020 was interrupted by the COVID-19 pandemic.A community-supported central kitchen model for SFPs is a relatively novel form of technology transfer by local NGOs. The model combined in-school feeding with decentralized implementation in the Philippines, where LGUs have political and financial decision-making space.At the local level, implementation created and strengthened multisectoral collaborative networks between the communities, schools, and LGUs, and fostered a culture of evidence-based policy making and civil engagement. The model’s success was attributed to strong community support for the central kitchen, mobilized into a steady pool of volunteers, embedding the program in the city’s and municipalities’ social networks. Public participation in local policy making compelled local government investment in adjacent holistic health and nutrition interventions by rallying nonhealth sectors to create new systems for multisectoral collaboration. Operations were sustained despite changes in political leadership through both formal and informal accountability mechanisms facilitated by transparent monitoring and evaluation.From the local to national level, vertical accountability was fostered by designating focal persons for feeding operations instead of increasing teachers’ workloads. Feeding coordinators collected feedback from schools, students, and volunteers, relaying information to the kitchens and LGUs. Daily operational reports were filled out by kitchen staff. Forms were collected by the LGU and submitted to DepEd. These were used in DepEd’s annual monitoring reports, submitted to and evaluated by the Office of the President and Congress as stipulated in the implementing rules and regulations of the NFP Law (Section 10).,,,The central kitchen SFP model envisioned multisectoral, community-led action from its inception. While a wide body of research,First, community-based interventions have been increasingly recognized as a vital component of health promotion. Community buy-in was crucial to sustaining interest in the program, as parent volunteers are necessary even in traditional SFPs. Community members, including parents of non-participants, were more inclined to volunteer in support of the program when it was attached to the LGU. As the program matured, social relationships sustained volunteer interest after a new LCE was elected. Civil participation brings nuanced knowledge, social trust, and formal and informal regulation to health programs.Community buy-in was crucial to sustaining interest in the program, as parent volunteers are necessary even in traditional SFPs.Second, civil clamor for health interventions such as the SFP is important, especially in decentralized health systems like that of the Philippines where LCEs are elected officials who may not necessarily prioritize health.,Third, strong leadership demonstrated by local leaders was complemented by their openness to feedback and support for evidence-based innovations to the model. While funding sustainability for the program is enshrined in national law,Strong leadership demonstrated by local leaders was complemented with an openness to feedback and support for evidence-based innovations to the model.The roles played by communities in program advocacy, operations, and accountability emphasize the need for community-based interventions to promote local ownership and allow room for nuanced variations to bring about a sense of agency and empowerment. As the model helped inform major provisions in the NFP Law, the case study presents supporting evidence for the use of central kitchens in SFPs, continued engagement of LGUs in executing national policies, and the institutionalization of hiring and training focal persons to handle multisectoral, multilevel health programs when implementing the law in subsequent sites.Given the study’s focus on community-led health interventions, only 2 implementation sites of the many central kitchens established by the NGOs were chosen. These were the biggest and first city- and province-wide operations, completely sustained by their local governments and communities. Though their experiences may not easily be generalizable to sites that did not manage to secure full community or LGU support, findings provided a picture of the confluence of factors necessary for success, as well as how challenges were overcome at the pilot, development, and mature phases of implementation. The inclusion of 1 urban and 1 rural site represented possible structural differences that may have affected implementation.Survey data, particularly dietary recalls, were sensitive to recall bias.As the research aimed to analyze the processes of a novel intervention involving multisectoral coordination, a full impact analysis comparing central kitchen model feeding meals with those of traditional SFPs was not undertaken. Qualitative data were more appropriate to understand coordination channels, accountability mechanisms, and program evolution in the different sites. As implementers such as local government officials and school administrators were included in FGDs, data may have been susceptible to social desirability bias.Locally led and operated central kitchens are a multisectoral investment that can spur health, education, and social welfare interventions. The experiences of 2 successful large-scale implementation sites present a model for improving diet and health, empowering civil society, and holding groups with a variety of interests accountable for multisectoral action in decentralized governments. Local-initiated innovations to traditional social programs increase acceptability and appropriateness. Operational sustainability was attributed to affording communities agency to provide feedback and gain ownership over program activities, embed volunteer pools in social networks, and organize demand for related services from their local politicians. Support and regulation from the national government in funding and accountability standards served as a foundation that enabled local governments to modify and augment the program according to their communities’ needs. Beyond the cost-effectiveness of constructing a large-scale central kitchen, the model institutionalized multisectoral coordination channels that may serve as a template for how other social services can be scaled and implemented in devolved settings.