Presenter Disclosures

Presenter Disclosures

National ALS Registry ALS Research Counts on You Paul Mehta, MD Principal Investigator National ALS Registry www.cdc.gov/als University of Kansas Medical Center Department of Neurology Grand Rounds 10/20/2017 Division of Toxicology and Human Health Sciences Environmental Health Surveillance Branch Disclosures None The findings from this presentation are of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (CDC/ATSDR). Outline of Presentation

Registry does more than count ALS cases Methodology Prevalence of ALS in the United States Surveys/Findings Notification Mechanism (Connecting PALS & Researchers) Registry publications National ALS Biorepository now Live! Funding research CDC Public Health Grand Rounds April 18, 2017 ALS CME Available 2017 Activities Conclusions/Questions Registry Does More than Just Count ALS Cases ALS Research Counts on You! U.S. ALS Registry Act Enacted as Public Law 110-373 (October, 2008)

Directed CDC/ATSDR to create a populationbased ALS registry for the U.S. Does not make ALS a notifiable disease National ALS Registry launched in Oct, 2010 Registry purposes (as specified by the Act) Describe incidence and prevalence of ALS Describe the demographics of ALS patients Examine risk factors for the disease National ALS Registry Methodology * Medicare, Medicaid, Veterans Administration ** Algorithm: ICD code, frequency of neurological visits, Rx drug usage Findings from the Second Report Covers ONLY from January 1, 2012 December 31, 2013 In 2012 and 2013, 14, 713 and 15,908

persons were identified as definite ALS, respectively. Includes national databases and portal = Registry Estimated ALS prevalence rates: 2012: 4.7 cases of ALS per 100,000 persons 2013: 5.0 cases of ALS per 100,000 persons ALS continues to be more common in Whites, males, and persons aged from 6069 Lowest number of ALS, Ages 18 39 and > 80 years Males had a higher prevalence than females Findings from the Second Report Continued Prevalence rates by age group, 2012-2013: Findings from the Second Report Continued

Prevalence rates by race, 20122013: 2012: whites and blacks were 5.0 and 2.4 cases per 100,000 2013: whites and blacks were 5.3 and 2.4 cases per 100,000 Third National ALS Prevalence Report Will be published in MMWR Weekly Report Cover calendar year 2014 Time line is Fall 2017 Finalizing and validating data from the National Death Index (NDI) Whats new? Include hospice data from Medicare Increase case ascertainment/counts Initial observations Registry is capturing more ALS cases from databases

Prevalence is leveling or slightly increasing Disease demographics and age groups affected are unchanged DOES NOT mean the number of ALS cases is increasing in the United States improved Risk Factor Surveys-Taken After Registration Survey (n=17) Release Date No. Completed Demographics October, 2010 7830 Occupational history October, 2010 7129 Military history

October, 2010 6991 Smoking and alcohol history October, 2010 6878 Physical activity October, 2010 6623 Family history of neuro. diseases October, 2010 6458 Disease progression (ALSFRS) October, 2010 6491 Clinical data (e.g., devices used, body onset) November, 2013

2504 Open-ended etiological questions November, 2013 2294 Lifetime residential history May, 2014 2651 Lifetime occupational history May, 2014 2615 Residential pesticide use May, 2014 2448 Hobbies with toxicant exposures August, 2014 2203 Caffeine consumption

August, 2014 2066 Reproductive history (women) August, 2014 1171 Health insurance status December, 2014 1765 Head and neck injuries December, 2014 1743 --- 69,860 Total (as of 10/16/2017) Survey Analyses Published preliminary results on surveys 1-6

Nearly half of survey respondents were ever smokers compared with nearly 41% of adults nationally. The majority were light drinkers. Nearly one-quarter of survey respondents were veterans compared with roughly 9% of US adults nationally. Industries in which respondents were employed for the longest time were Professional and Scientific and Technical Services. Findings consistent with other published studies on ALS risk factors. Analyzing survey 7, disease progression Examining surveys 15 and 17 (health status and clinical module) Reviewing survey 16, open-ended questions on ALS causes Research Notification System Patient recruitment for research can be difficult Approx. 95% of Registry PALS want to

participate in research Registry links PALS with scientists who are recruiting for research (e.g., clinical trials, studies) Domestic and international researchers are using Research Notification Mechanism * Researchers will ultimately determine eligibility to participation in studies Research Notification Mechanism CDC IRB approval Not needed IRB approval by applicants institution

Search criteria Age Sex Time since dx. City, state, regional, and national Less than 4 weeks for review/approval Research Notifications Study Name (n=30) Institution Investigator Risk Factor Analysis in ALS Medical University of SC David Stickler, MD Phase II/III Trial of Arimoclomol in SOD1+ Familial ALS

University of Miami Michael Benatar, MD, PhD Mindfulness, psychological well-being, and physical degeneration in people with ALS Harvard University Ellen Langer, PhD Spatial Analysis of ALS in Florida, Ohio, New Hampshire, and Vermont Dartmouth-Hitchcock Medical Center Elijah Stommel, MD, PhD Mexiletine treatment of muscle cramps in ALS University of California, Davis Bjrn Oskarsson, MD Epidemiologic Risk Factors &Genetics of ALS

University of Michigan Eva Feldman, MD, PhD Exp. Treatment of Bulbar Dysfunction in ALS Center for Neurologic Study Richard Smith, MD The Natural History and Biomarkers of C9ORF72 ALS and Frontotemporal Dementia (FTD) National Institutes of Health/NINDS Mary Kay Floeter, MD, PhD Developing a Satellite ALS Center at a Remote Site Incorporating Regional Resources &Telemedicine University of Kentucky Edward Kasarskis, MD, PhD Research Notifications (cont.)

Study Name (n=30) Institution Investigator Prospective Epi. Study in a Large National ALS Registry Cohort to Identify ALS Risk Factors Columbia University Medical Center Hiroshi Mitsumoto, MD, DSc VA Biorepository Brain Bank ALS Study VA Boston Healthcare System Neil W. Kowall, MD Questionnaire of cramps and pain in ALS University of California, Davis Bjrn Oskarsson, MD Assessing pain in ALS Penn State Hershey Medical Center

Zachary Simmons, MD NeuRx Diaphragm Pacing System (DPS) study Barrow Neurological Institute Jeremy M. Shefner, MD, PhD An online questionnaire for research into ALS University of Sydney Roger Pamphlett, MD, MB ALS and Genetic Testing: A Perspective from the ALS Community The Ohio State University Jennifer Roggenbuck, MS Speech Motor Impairments MGH Institute of Health Professions Jordan Green, PhD RDCRN Contact Registry for the CReATe Consortium

University of Miami Michael Benatar, MD, PhD Study to Evaluate the Sensitivity, Specificity, and Overall Accuracy of an ALS Diagnostic Test Iron Horse Diagnostics, Inc. Andreas Jeromin, PhD Phase 2 Pharmacodynamic Study of Ezogabine on Neuronal Excitability in ALS Massachusetts General Hospital Brian J. Wainger, MD, PhD Research Notifications (cont.) Study Name (n=30) Institution Investigator VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices after Treatment for a Year) Cytokinetics, Inc.

Jinsy Andrews, MD Methodology Study of Novel Outcome Measures to Assess Progression of ALS Biogen, Inc. Nazem Atassi, MD A Phase 2 Study of NP001 in Subjects with ALS and Evidence of Elevated Systemic Inflammation Neuraltus Pharmaceuticals, Inc Gilbert Block, MD, PhD Mayo Clinic Jacksonville Kevin Boylan, MD Massachusetts General Hospital - Neurological Clinical Research Institute (MGH-NCRI) Katharine Nicholson, MD Barrow Neurological Institute Jeremy Shefner, MD

Treatment of FUS-Related ALS with Betamethasone The TRANSLATE Study University of Kentucky Edward J. Kasarskis, MD, PhD Determining the half-life of SOD1 in the CSF Washington University (St. Louis) Timothy Miller, MD, PhD University of Washington Michael D. Weiss, MD Biospecimen Collection to Investigate the Causes of ALS Microbiome Assessment in People with ALS ALS Testing through Home-Based Outcome Measures >100,000 email notifications sent to date Mexiletine in Sporadic Amyotrophic Highlighted Notifications Using the Registry

Registry helped to recruit for notable clinical trials: Cytokinetics, Inc. : Tirasemtiv, Phase III clinical trial; helps to reduce muscle fatigue Neuraltus Pharmaceuticals, Inc: NP001, Phase II, helps to slow down ALS by reducing inflammation Epidemiological/Risk Factor/Clinical Studies Columbia University: ARREST ALS study, examine the relationship between oxidative stress (OS) and ALS as well as combined exposures on development of ALS, including environmental, occupational, lifestyle, dietary, and psychological risk factors. Massachusetts General Hospital: microbiome assessment, role of gut microbiota in the development of diseases such as ALS, linked to inflammation. Barrow Neurological Institute: ALS testing at home, travel requirement may prevent participation in studies, Highlighted Notifications Using the Registry Epidemiological/Risk Factor/Clinical Studies Washington University (St.Louis): mutations in the SOD1 gene are known to cause some forms of familial ALS. Researchers are developing a treatment to reduce the level of SOD1 in familial ALS, but need to know more about how long SOD1 stays in the body ("half-life") to help determine if the new treatment is effective.

University of Washington: whether the drug mexiletine works to calm over-excited nerves and brain cells in people with ALS. We hope that this will also slow down how quickly the disease advances. 60 people with ALS will be enrolled to take part in the study. Taking part means participating in up to four study visits and one telephone call over about eleven weeks. 2017 Research Publications Over 10 Peer-reviewed publications/abstracts (note Registry pays for open-access, when possible) Abstracts presented at AAN, NEALS, International ALS/MND Symposium Journal Articles: National ALS Biorepository is Live! ATSDR completed 4 year biorepository pilot study Launched in January 2017 Enrollment has begun Must enroll in the Registry to participate

Past enrollees need to re-consent Annual sample collection goals: 675 in-home collections 325: saliva, urine, blood (requires phlebotomist) 350: saliva kits (mailed to PALS) 10 post-mortem collections Global Unique Identifier (GUID) National ALS Biorepository Biorepository will significantly differ from others by: linking extensive risk factor survey data with biosamples being nationally representative (e.g., beyond referral centers) being user-friendly to PALS (e.g., use in-home phlebotomists to collect samples) collecting specimens specifically for biorepository (i.e., not use leftover study samples to constitute biorepository) containing pre/post mortem samples in one central biorepository

Largest collection of pristine ALS samples for research, e.g., genetics, biomarkers, disease progression. National ALS Biorepository Overview Extramural Research Funding ATSDR is funding extramural research to learn more about ALS etiology and risk factors 12 research studies have been funded to date Info gleaned also will help ATSDR prioritize topics for future risk factor surveys

Future funding is Extramural ALS Research Funded by ATSDR Study Name (n=13) Institution Investigator Funding period Epidemiology of ALS Harvard University Marc Weisskopf, PhD, ScD 2012 - 2013 Large-scale genome-wide association study of ALS National Institutes of Health Bryan Traynor, MD, PhD 2012 - 2013 Gene-environment interactions in ALS

Northwestern Univ. Teepu Siddique, MD 2012 2013 A Prospective Comprehensive Epidemiologic Study in a Large Cohort in The National ALS Registry: A Step to Identify ALS Risk Factors Columbia University Medical Center Hiroshi Mitsumoto, MD, DSc 2013 2017 Identification and Validation of ALS Environmental Risk Factors University of Michigan Eva Feldman, MD, PhD 2013 2017 Ecologic Study to Evaluate Spatial Relationships between ALS and Potential Environmental Risk Factors

Dartmouth College Elijah W. Stommel, MD, PhD 2014 2016 Prospective study of biomarkers and risk factors for ALS incidence and progression Harvard School of Public Health Alberto Ascherio, MD, DrPH 2014 2015 Case-Control Studies Nested in National ALS Registry to Evaluate Environmental Risks Columbia University Medical Center Hiroshi Mitsumoto, MD, DSc 2015 - 2018 Antecedent Medical Conditions and Medications: Associations with the Risk and Prognosis ALS Stanford University

Lorene Nelson, PhD ALS Risk in Latin Americans- A population based case control comparative study with 3 European population based cohorts Trinity College Dublin, Ireland Orla Hardiman, MD, PhD 2016 - 2018 A Population-Based Ohio ALS Repository and a Case-Control Study of ALS Risk Factors Dartmouth College Elijah Stommel, MD, PhD 2016 - 2018 Environmental risk factors and geneenvironment interactions in ALS risk and progression University of Miami Michael Benatar, MD, PhD 2016 - 2018

Identification and Characterization of Potential Environmental Risk Factors for ALS Using the ATSDR ALS Registry Cases and a Control Population University of Pittsburgh at Pittsburgh Evelyn O. Talbott, DrPH. 2015 - 2018 2017-2020 Highlighted Research Dartmouth College: Chemicals suggested to cause ALS are pesticides, algal blooms in lakes (green scum), and chemicals released by factories, contact all the people with ALS living in Northern and Central Ohio and ask them to answer a series of questions about what they may have been exposed to. Stanford University: There is little known about how chronic medical conditions and drugs may impact susceptibility to ALS. This study will look at the role of hyperlipidemia, diabetes, autoimmune

diseases, as well as the drugs used to treat these disorders, as both risk and prognostic factors for ALS. Trinity College-Dublin, Ireland: The purpose of this study is to compare two populations with different genetic and environmental risks. It has been suggested that the Hispanic population in North America has lower rates of ALS. In effort to understand if and why the Hispanic population in North and South America is protected from ALS, we will compare this population to Europeans. CDC Public Health Grand Rounds First-ever for ALS and ATSDR; April 18, 2017 Topic: National Amyotrophic Lateral Sclerosis Registry: Impact, Challenges, and Future Direction 4 speakers: o Kevin Horton, DrPH: history, purpose, and need for the Registry o Paul Mehta, MD: epidemiology, research initiatives, Biorepository o Edward Kasarskis, MD: neurologist perspective o Edward Tessaro: patient perspective Viewer metrics Over 20,000 Facebook live viewers; Post Reach: 222,729 (287% above average reach of a Facebook post from CDC) 209,506 organic reach (total number of unique people who received post)

Beyond the Data session archived on ALS Continuing Education Module 1.5 contact hours of free CE Course was developed for physicians (primary care physicians and neurologists without ALS expertise) as well as other public health professionals 2017 Activities Published funding opportunity announcement (FOA) Identify and Characterize Potential Environmental Risk Factors for Amyotrophic Lateral Sclerosis (ALS) and Evaluate Their Impact on ALS Disease Incidence and Progression Funded one grant Working on new FOA for FY18, released in the Fall Update Registry website Responsive, mobile friendly design user testing started

Launch September 2017 Spanish site for ALS information, registration, and completion of surveys Developed new Registry informational video Describe benefits and facets of the Registry to 2017 Activities 3rd MMWR Report Anticipated release in the fall 2017 Calendar year 2014 Manuscripts in development Access to ALS care, using ALSA and MDA clinic locations ALS survival/disease progression modeling National ALS mortality Comparison of Registry data to state and metro data Capture/Recapture Educational and promotional outreach activities to general neurologists (non-referral) Open-ended survey: What caused my ALS?

Continued evaluation Registry risk factor data Currently almost 70,000 completed surveys Summary The National ALS Registry is: The 1st & only population-based ALS registry for the U.S. Fulfilling Congressional mandate Registry has added National ALS Biorepository Sample collection from PALS Sample dissemination to researchers Registry has added GUID Registry continues to fund research on ALS risk factors and etiology Registry seeks to have a larger internet presence Responsive design/web buttons

Comments/Questions? www.cdc.gov/als For more information please contact Agency for Toxic Substances and Disease Registry 4770 Buford Hwy. NE, Chamblee, GA 30341 Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 E-mail: [email protected] Web: www.atsdr.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Division of Toxicology and Human Health Sciences Environmental Health Surveillance Branch

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