Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

Multiobjective Optimization-Aided Decision-Making System for Large-Scale Manufacturing Planning.

This work is geared toward a real-world manufacturing planning (MP) task, whose two objectives are to maximize the order fulfillment rate and minimize the total cost. More important, the requirements and constraints in real manufacturing make the MP task very challenging in several aspects. For example, the MP needs to cover many production components of multiple plants over a 30-day horizon, which means that it involves a large number of decision variables. Furthermore, the MP task's two objectives have extremely different magnitudes, and some constraints are difficult to handle. Facing these uncompromising practical requirements, we introduce an interactive multiobjective optimization-based MP system in this article. It can help the decision maker reach a satisfactory tradeoff between the two objectives without consuming massive calculations. In the MP system, the submitted MP task is modeled as a multiobjective integer programming (MOIP) problem. Then, the MOIP problem is addressed via a two-stage multiobjective optimization algorithm (TSMOA). To alleviate the heavy calculation burden, TSMOA transforms the optimization of the MOIP problem into the optimization of a series of single-objective problems (SOPs). Meanwhile, a new SOP solving strategy is used in the MP system to further reduce the computational cost. It utilizes two sequential easier SOPs as the approximator of the original complex SOP for optimization. As part of the MP system, TSMOA and the SOP solving strategy are demonstrated to be efficient in real-world MP applications. In addition, the effectiveness of TSMOA is also validated on benchmark problems. The results indicate that TSMOA as well as the MP system are promising.

Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.

Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.This article is highlighted in the In This Issue feature, p. 211.

FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements.

FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, oral inhibitor of FGFR1-3, has demonstrated efficacy and safety in a Phase II study of patients with previously treated locally advanced/metastatic CCA harboring FGFR2 fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with FGFR2 rearrangements (NCT03656536). The primary end point is progression-free survival; secondary end points are objective response rate, overall survival, duration of response, disease control rate, safety and quality of life. Clinical Trial Registration: NCT03656536 (ClinicalTrials.gov).

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.

Fast Covariance Matrix Adaptation for Large-Scale Black-Box Optimization.

Covariance matrix adaptation evolution strategy (CMA-ES) is a successful gradient-free optimization algorithm. Yet, it can hardly scale to handle high-dimensional problems. In this paper, we propose a fast variant of CMA-ES (Fast CMA-ES) to handle large-scale black-box optimization problems. We approximate the covariance matrix by a low-rank matrix with a few vectors and use two of them to generate each new solution. The algorithm achieves linear internal complexity on the dimension of search space. We illustrate that the covariance matrix of the underlying distribution can be considered as an ensemble of simple models constructed by two vectors. We experimentally investigate the algorithm's behaviors and performances. It is more efficient than the CMA-ES in terms of running time. It outperforms or performs comparatively to the variant limited memory CMA-ES on large-scale problems. Finally, we evaluate the algorithm's performance with a restart strategy on the CEC'2010 large-scale global optimization benchmarks, and it shows remarkable performance and outperforms the large-scale variants of the CMA-ES.

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors.

LESSONS LEARNED: Itacitinib in combination with nab-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents. BACKGROUND: Cytokine-mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer. METHODS: This phase Ib/II dose-optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel plus gemcitabine in adults with treatment-naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab-paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony-stimulating factor, de-escalations of itacitinib to 300 mg once daily (QD), nab-paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2. RESULTS: Among 55 patients in Part 1, 6 developed seven hematologic dose-limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de-escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%). CONCLUSION: Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.

A Placebo-Controlled Phase II Study of Ruxolitinib in Combination With Pemetrexed and Cisplatin for First-Line Treatment of Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer and Systemic Inflammation.

BACKGROUND: Dysregulation of the Janus kinase (JAK)/signal transducers and activators of transcription pathway contributes to abnormal inflammatory responses and poor prognosis in non-small-cell lung cancer (NSCLC). We evaluated the JAK1/JAK2 inhibitor ruxolitinib plus pemetrexed/cisplatin first-line in patients with stage IIIB/IV or recurrent nonsquamous NSCLC with systemic inflammation (modified Glasgow prognostic score [mGPS] 1/2). PATIENTS AND METHODS: Part 1 was an open-label, safety run-in, in which we assessed ruxolitinib (15 mg twice daily [b.i.d.]) plus pemetrexed (500 mg/m2 intravenous, day 1) and cisplatin (75 mg/m2 intravenous, day 1). Ruxolitinib dose selection for part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. In part 2 patients were randomized to ruxolitinib or placebo (each plus pemetrexed/cisplatin). The trial terminated early for reasons unrelated to this trial. RESULTS: Fifteen patients enrolled in part 1 (median age, 64 years; 80% male, 80% mGPS 1) received ruxolitinib 15 mg b.i.d. plus pemetrexed/cisplatin. Median treatment duration was 140 days and no DLTs occurred in 11 evaluable patients. No new safety concerns arose when ruxolitinib was combined with pemetrexed/cisplatin. At study termination, 39 patients were randomized to ruxolitinib and 37 to placebo in part 2. Median treatment duration was 43 days. Response rate was 31% (12 of 39) with ruxolitinib and 35% (13 of 37) with placebo (all partial responses). CONCLUSION: Ruxolitinib 15 mg b.i.d. had an acceptable safety profile in combination with pemetrexed/cisplatin asfirst-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation. Early study termination limited the interpretation of efficacy data in the randomized phase II part of the study.

Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies.

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF).

The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82-4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial.

RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.

Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy.

OBJECTIVES: Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. METHODS: In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). RESULTS: Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. CONCLUSIONS: Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant.

Optical rogue waves associated with the negative coherent coupling in an isotropic medium.

Optical rogue waves of the coupled nonlinear Schrödinger equations with negative coherent coupling, which describe the propagation of orthogonally polarized optical waves in an isotropic medium, are reported. We construct and discuss a family of the vector rogue-wave solutions, including the bright rogue waves, four-petaled rogue waves, and dark rogue waves. A bright rogue wave without a valley can split up, giving birth to two bright rogue waves, and an eye-shaped rogue wave can split up, giving birth to two dark rogue waves.

Are clusters of mental retardation correlated with clusters of developmental delay?

Mental retardation (MR) is a subset of developmental delay (DD), a broader classification of childhood disability. The purpose of this study was to determine if clusters of these two conditions were statistically significantly correlated. The residential addresses of 81,935 Medicaid insured pregnant women during each month of pregnancy were used to identify clusters of MR and DD in their children. Correlations between MR and DD were computed based on the sets of P-value surface from selected centroid points, where the P-value for cumulative relative risk of MR and DD was known. The correlations are quite small for all the 10 gestational months for which maternal addresses were available, but they are all statistically significant. This indicates MR and DD are correlated, but they are not linear. When MR was used as the centroid point to identify a cluster the only correlations that were statistically significant were for gestational month 5 and 6 with correlation 0.14 (P = 0.007) for both months. When the centroid points were selected based on the significance of risk of DD, the correlations between MR and DD are not statistically significant for any month. Correlation between MR and DD based on the sets of P-value surfaces from 4 MR clusters are significant in gestational month 5, 6 and 7 with correlation 0.17 (P = 0.047), 0.16 (P = 0.060) and 0.17 (P = 0.044), respectively. Our finding suggests that locations of high risk for the more severe condition, MR, also identify a spatial area where less severe cases of DD might be present, however the reverse is not the case.

Teaching medical students about disability in family medicine.

We investigated whether a unique didactic focusing on delivering health care to patients with disabilities (PWDs) impacts medical students' knowledge of specific disabilities and related concerns, attitudes about barriers to this populations' health care, and behavior during typical primary care visits with PWDs. A 90-minute session for students during their third-year family medicine clerkship addressed clinical considerations for patients with mobility and cognitive impairments. Questionnaires were administered to students at the beginning and completion of the clerkship. Analyses of 71 matched questionnaires reveal that knowledge and attitudes were positively impacted.

PI3K/AKT mediated p53 down-regulation participates in CpG DNA inhibition of spontaneous B cell apoptosis.

The unmethylated CpG DNA can prevent spontaneous apoptosis of B cells. However, the precise mechanisms by which CpG DNA blocks apoptosis remain unclear. In this study, we showed B cell apoptosis was significantly inhibited by addition of CpG DNA. Treatment of CpG DNA could reduce the expression of caspase 3, increase IAP and Bcl-xL expressions, and inhibit p53 protein expression which level was increased in B cell spontaneous apoptosis at 24 h. AKT kinase activity was increased with the incubation of CpG DNA. The wortmannin and Ly294002 could abrogate the protection of B cell from apoptosis by CpG DNA. The up-regulations of Bcl-xL and IAP by CpG DNA were not inhibited when blocking PI3K by specific inhibitor Ly294002, while the inhibition of p53 by CpG DNA could be blocked by Ly294002. These results demonstrated that the inhibition of spontaneous B cell apoptosis by CpG DNA was correlated to up-regulation of Bcl-xL, IAP and down-regulation of p53 and caspase 3. CpG DNA inhibition of p53 is mediated through PI3K/AKT signaling.

A spatial analysis of mental retardation of unknown cause and maternal residence during pregnancy.

Spatial analysis is useful for the identification of areas of elevated risk of adverse health outcomes and generation of hypotheses. Identification of clusters based on maternal residence during pregnancy provides an important tool to investigate risk exposures. However, even though mental retardation (MR) is a substantial public health problem, there are no previous analyses of spatial clustering of childhood MR using individual case data. In this paper, we examine the use of the Bayesian hierarchical modeling approach in the analysis of MR clustering. We used data from South Carolina Medicaid and birth certificates, in which address codes for each month of pregnancy are available. MR cases with unknown cause were identified in the study population. A Bayesian local likelihood cluster modeling technique was applied to compute the relative risk of MR and its corresponding P-value for each geo-coded location, and the P-value surface was contoured as a heat image to identify the MR clusters. The characteristics of the study population were analyzed using chi-square tests and the results confirm that clustering does occur for MR. The shapes of the identified MR clusters were found to be irregular and the observed MR rate in the identified MR cluster area was found to be double the rate for the larger South Carolina region. The descriptive analysis of study population characteristics showed that the children with MR were more likely to be male and had mothers who were older than 34 years at the time of birth as well as being African American, preterm and of low birth weight compared to children without MR.