SSB National ALS Registry

National Amyotrophic

Lateral Sclerosis (ALS) Registry

OMB Control No. 0923-0041 (Expiration Date: 11/30/2019)

Revision

Supporting Statement Part B –

Collections of Information Employing Statistical Methods

Principal Investigator:

Paul Mehta, MD

Agency for Toxic Substances and Disease Registry

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-0556

Fax: 770-488-1537

Email: [email protected]

Date: August 12, 2019

Table of Contents

List of Attachments 3

B.1. Respondent Universe and Sampling Methods 4

B.2. Procedures for the Collection of Information 8

B.3. Methods to Maximize Response Rates and Deal with No Response 10

B.4. Test of Procedures or Methods to be Undertaken 12

B.5. Individuals Consulted on Statistical Aspects and Individuals Collecting and/or Analyzing Data 12

References 13

List of Attachments

Attachment 1 Authorizing Legislation: Public Law No. 110-373

Attachment 2 60-Day Federal Register Notice

Attachment 3 Summary of Revisions

Attachment 4 ALS Case Validation Questions

Attachment 5 ALS Case Registration Form (screenshots)

Attachment 6 Approved Surveys (screenshots) – including 16 Voluntary Survey Modules and Disease Progression Survey

Attachment 6A ALS Functional Rating Scale-Revised (ALSFRS): Scoring Sheet

Attachment 6B New Sports Participation Survey Module

Attachment 7 Privacy Statement

Attachment 8 Consent Forms

Attachment 8A National ALS Registry

Attachment 8B National ALS Biorepository (Biospecimens)

Attachment 8C National ALS Biorepository (Postmortem)

Attachment 8D National ALS Biorepository Consent Form (Saliva)

Attachment 9 CDC IRB Approval Letters

Attachment 10 Privacy Impact Assessment

Attachment 11 Researcher Forms

Attachment 11A ALS Registry Research Application Form

Attachment 11B Annual Update

Attachment 12 ALS Biorepository Forms and Instructions

Attachment 12A ALS Biorepository Specimen Processing Form

Attachment 12B ALS Biorepository Saliva Collection Instructions

Attachment 13 Service Organization Forms

Attachment 13A Outreach Reporting Form for Chapters and Districts

Attachment 13B Outreach Reporting Form for National Offices

Attachment 14 Biorepository Pilot Study Report

Part B. Collections of Information Employing Statistical Methods

This data collection does not involve statistical methods; however we have described the respondents. There are no proposed changes to recruitment methods.

B.1. Respondent Universe and Sampling Methods

This activity is surveillance; respondents are not sampled. Furthermore, no sample selection is involved in this registry. The Registry will pull in both individuals with ALS from existing administrative data and will allow cases to self-identify. However, there will be some selection for the biorepository component of the Registry due to budget constraints. Individuals asked to participate in the biorepository will be selected from PALS who enroll in the Registry and express and interest in learning more about the biorepository. To better address the congressional mandate to examine genetic and environmental risk factors that may cluster by geographic area, we will select a convenience sample from those who are interested in the biorepository proportional to state population and with at least one person from each state. We will recruit from the harder to fill states, e.g., Wyoming, Rhode Island, first and then distribute the cases throughout the other states. Because recruitment tends to get individuals from the same town to enroll during the same time period, selection in states where we are recruiting multiple participants will be distributed across the states in any given month by stratifying those interested in participating in each state by city and taking a systematic sample from the different geographic areas.

The primary purpose of the Registry is to improve estimates of likely prevalence of ALS and provide basic demographic information including, age, race, sex and geographic area. The tabulation of risk factor information required by Congress is for descriptive purposes only. The following table includes the distribution of selected risk factor data.

Tabulation of Selected Risk Factor Data, October 18, 2010 – December 31, 2017

	No.	%
Smoking Status*
Current Smoker	464	17.4
Former Smoker	2192	65
Nonsmoker	2734	50.6
Ever Smoker	2662	49.3
Smoking Duration
< 10 years	570	21.6
10- <25 years	993	37.7
25- <40 years	705	26.8
40+ years	366	13.9
Smoking Intensity
< 5 pack-years	572	21.7
5 to <15 pack-years	650	24.8
15+ pack-years	1409	53.5
Alcohol Consumption Status
Current Drinker	2352	54.7
Former Drinker	1847	45.3
Nondrinker	1071	19.8
Ever Drinker	4311	79.9
Drinking Duration
< 10 years	1497	36
10- <25 years	960	23.1
25- <40 years	509	12.3
40+ years	1190	28.6
Drinking Intensity
Light Drinker	3568	85.5
Moderate Drinker	464	11.2
Heavy Drinker	139	3.3
Military Service History
Veterans	1243	22.7
Nonveterans	4219	77.1
Branch of Military Service
Army	486	36.8
Navy	290	22
Marines	95	7.2
Air Force	260	19.7
Reserves	164	12.4
Coast Guard	24	1.8
More than one branch of military service	-	-
Deployment to a War Arena
Yes	401	32.4
No	838	67.6
Employment Status
Full-time employed	610	17.4
Part-time employed	168	4.8
Retired	1163	33.1
Disabled	1351	38.5
Full-time student	5	0.1
Homemaker	64	1.8
Unemployed	87	2.5
Other	61	1.7
Job Title Held for the Longest Time (Top 10)
Teacher, professor or educator	476	8.7
Physician, nurse, dental or health care worker	400	7.3
Secretary, administrative assistant or receptionist	271	5
Engineer, architect or draftsperson	264	4.8
Retail salesperson, sales clerk, or sales representative	217	4
Manufacturing laborer, production worker, or assembler/fabricator	194	3.6
Accountant, auditor, or bookkeeper	190	3.5
Supervisor or manager of financial or marketing workers	158	2.9
Chief executive or owner	157	2.9
Supervisor or manager of manufacturing or production workers	124	2.3
Industry Worked in for the Longest Time (Top 10)
Professional, Scientific, and Technical Services	638	12.2
Health Care and Social Assistance	565	10.8
Educational Services	563	10.8
Manufacturing (Metal, Electrical, Transport, Professional)	415	7.9
Other Services (except Public Administration)	357	6.8
Construction	355	6.8
Retail Trade I (Cars, Gas, Furniture, Electronics, Food-Beverage, Clothing)	339	6.5
Finance and Insurance	297	5.7
Manufacturing - (Paper, Printing, Chemicals, Petroleum, Leather, Lumber, Stone)	233	4.5
Transportation and Warehousing I (Air, Rail, Water, Ground, Pipeline)	179	3.4
Years of Employment at Longest Held Occupation
<= 10 years	759	13.9
10 < time <= 20 years	1591	29.2
20 < time <=30 years	1615	29.6
> 30 years	1486	27.3

As the Registry matures and more individuals self-register, the information could be used for research (i.e., hypothesis generation). ATSDR allows approved researchers to provide registrants with information about ongoing studies for which they might be eligible. ATSDR plans to compare those individuals who self-register with those identified in the administrative data. ATSDR will then begin to analyze the data provided in the surveys. The National ALS Registry uses a two-pronged approach to identify prevalent cases of ALS in the United States. The first approach used to identify prevalent cases relies on existing administrative data (from the Centers for Medicare and Medicaid Services, the Veterans Health Administration [VHA], and the Veterans Benefits Administration [VBA]). A pilot tested algorithm is applied to the administrative data that identifies persons with ALS on the basis of encounter codes such as having ALS listed as a code in the visit record or having such a code and having seen a neurologist, a death certificate listing ALS as a cause or contributing cause of death, and prescription for Riluzole.¹ The second approach, which was launched to the public on October 19, 2010, uses a secure web portal (https://www.cdc. gov/als) to identify cases that are not included in the national administrative databases. This approach allows patients to self-identify and enroll in the National ALS Registry if screening criteria are met. An additional advantage of this approach is those who self-enroll in the Registry can take brief surveys that are used to evaluate possible risk factors for ALS.² Information is merged into a single record for each person. Merging records for persons identified as having ALS from the administrative databases with those persons who enrolled in the National ALS Registry web portal creates a unique record after data are de-duplicated by using a combination of the last five digits of the person’s Social Security number, sex, month and year of birth, and first and last name. This process ensures that persons who are identified in both the administrative databases and the web portal, and those who have records in multiple years, are not counted twice.

In the third report published in the MMWR, November 2018, we report that during 2015, the Registry identified 16,583 persons who met the surveillance case definition of ALS. The estimated ALS prevalence rate was 5.2 cases per 100,000 U.S. population. Since the inception of the Registry, the pattern of characteristics (e.g., age, sex, and race/ethnicity) among persons with ALS have remained unchanged. Overall, ALS was more common among whites, males, and persons aged 60–69 years. The age groups with the lowest number of ALS cases were persons aged 18–39 years and those aged ≥80 years. Males had a higher prevalence rate of ALS than females overall and across all data sources. These findings remained consistent during October 2010–December 2015.

Per the terms of clearance, the following limitations were included in the MMWR:

‘”The findings in this report are subject to at least three limitations. First, because ALS is not a nationally notifiable disease, the possibility of underascertainment exists and the three databases from which the majority of cases are identified are not representative of the U.S. population. The databases include a large percentage of persons aged ≥50 years; however, both the U.S. Department of Veterans Affairs and Medicare have special considerations that allow persons with ALS to receive benefits for ALS without waiting periods or meeting age requirements, increasing the likelihood that they are in the databases. In addition, the Registry seeks to use capture/recapture methodology for future reports to estimate the percentage of missing ALS cases, as well as to improve self-enrollment by increasing awareness and outreach in underrepresented populations identified in certain geographic areas (^3,4). Second, although every attempt was made to deduplicate files, differences in fields collected from the various sources, misspellings of names, and data entry errors could have prevented records from merging correctly. However, it is unlikely that this occurred in numbers sufficient to affect the overall conclusions. Finally, the calculation of ALS incidence with Registry data is not possible at this time because the date of diagnosis is not captured through the large administrative database approach, and cases without a date of diagnosis account for 79.6% of cases in the Registry.”

B.2. Procedures for the Collection of Information

ALS patients will be allowed to voluntarily register for the Registry. Case status will be validated using six questions standardized by the Veterans Administration and shown to correctly identify cases 93% of the time (Attachment 4). Once an individual passes validation, he will be permitted to register (Attachment 5). To enable the collection of additional information from registrants who volunteer, a series of short voluntary survey modules will be available for completion via a secure web portal (Attachment 6). All surveys are designed to be answered only once except for the disease progression survey (Attachment 6A – ALSFRS module only) which can be answered three times the first year and twice a year thereafter (rounded up to 3 times per year for burden estimation). It is anticipated that most participants would complete the disease progression survey 3-4 times at most because the average life expectancy of an individual diagnosed with ALS is 2-3 years and the disease is quite debilitating. For the disease progression survey we will use the ALS Functional Rating Scale-Revised (ALSFRS-R) (Attachment 6A – ALSFRS module only), a standard set of questions used by physicians to measure function overtime. Researchers have developed and tested a self-administered version of the ALSFRS-R which showed excellent reliability to change over time. This test is scored in a standard fashion (Attachment 6A).

Individuals will be consented prior to registering with the National ALS Registry and completing any survey modules. Participants will not be contacted to take surveys. For all surveys, the individual will have to visit the website and log in to his/her personal account. Therefore, if a participant does not want to take part any longer, he/she just doesn’t log in to the system.

In addition to fulfilling the two-part Congressional mandate, the Registry is designed to be a tool for ALS researchers. Now that the Registry has matured, ATSDR will make data and specimens available to approved researchers. A respondent type was added to allow researchers to access data and specimens collected by the Registry (Attachment 11A and 11B). For those who agree to participate in the in-home portion of the biorepository, we will schedule an appointment for a trained phlebotomist to come to their homes at a convenient time to collect the specimens (Attachment 12A). Because we have to get specimens to the lab the next day, appointments are only scheduled Monday through Thursday at a time that would allow the phlebotomist to deliver the specimens to a FedEx facility for next day shipping. For those who agree to provide a saliva specimen, we will mail them a self-collection kit with instructions for the collection and pre-paid postage to return the kit to the laboratory (Attachment 12B). In addition, ATSDR is also collaborating with ALS service organizations to conduct outreach activities through their local chapters and districts as well as on a national level. ATSDR will collect summary information on their outreach efforts in support of the Registry (Attachment 13A and 13B).

B.3. Methods to Maximize Response Rates and Deal with No Response

There is not a method to deal with non-response to joining the National ALS Registry because it is unknown who has ALS. ATSDR has used a multi-pronged approach for publicizing the existence of the Registry. First, ATSDR promoted the information on their ALS website www.cdc.gov/als. Second, ATSDR worked with two advocacy groups, the ALS Association (ALSA) and the Muscular Dystrophy Association (MDA), ALS Division, to promote the Registry with their constituents and on their respective websites http://www.alsa.org/research/ and http://mda.org/disease/amyotrophic-lateral-sclerosis. A monthly summary of outreach activities will be provided by the chapter or districts to the national organizations (Attachment 13A) who will report to ATSDR on a monthly basis (Attachment 13B). Third, ATSDR has worked with the NCEH-ATSDR Office of Communication to develop a media campaign which has been included in presentations at conferences, advertisements, and social media.

As such, it is likely that not all persons with ALS will register; it will be difficult to determine the extent of nonresponse bias among those who would not be expected to show up in the administrative data sources. In addition, because we are currently seeing only a 58% response rate for the “risk factor surveys” among those who do register, it is likely that there will be nonresponse bias. ATSDR will inform users of this likelihood, and promote the dataset for hypothesis generation rather than hypothesis testing.

Basic demographic variables such as age, race, and sex will be available on all individuals regardless of how they were identified. Individuals identified from administrative data will not have all of the OMB approved categories; however the self-reported data will have all OMB categories.

Because we hypothesize that the self-registration portion of the Registry is, and will continue to identify some individuals who are not identified in the administrative sources, we will compare ALS cases identified from administrative sources with those ALS cases who self-register. All Medicare, VHA, and VBA data are only available through CY2015. In addition, CY2015 is the most recent year that includes all data sources because of the lag in availability of data from CMS.

Individuals in the National ALS Registry are identified from national databases and self-registration. Those individuals who self-register are more likely to be younger (40-69 years of age) and female than those individuals identified in the national databases. This is likely a result of computer literacy and access. In addition to registering, registrants can provide additional information by taking short surveys. When comparing individuals who took at least one survey with individuals who took no surveys, there is little difference in age and no difference in sex between takers and non-takers.

Comparison of Registry Data by Source and Survey Status for CY2015

Registry								Portal*
	Total		Database Only		Portal			Survey Takers		Survey Non-Takers
Age	#	%	#	%	#	%		#	%	#	%
18-39	480	2.9	300	2.4	776	5.7		106	4.2	74	4.4
40-49	1462	8.8	925	7.5	180	15.3		307	12.3	229	13.5
50-59	3214	19.4	2126	17.2	536	28.9		662	26.5	420	24.8
60-69	4774	28.8	3740	30.2	1082	31		598	23.9	434	25.6
70-79	3953	23.8	3482	28.1	1032	14.7		269	10.8	202	11.9
80 +	1522	9.2	1412	11.4	471	3.4		50	2.0	60	3.5
Unknown	1178	7.1	402	3.3	110	1		509	20.4	276	16.3
Total	16583		12387		4196			2501		1695
Sex
Male	10098	60.9	7631	61.6	2467	58.9		1489	59.5	987	58.2
Female	6458	38.9	4738	38.3	1720	41.1		1012	40.5	708	41.8
Unknown	27	0.2	18	0.1				0	-	0	-
Total	16583		12387		4196			2501		1695
*Unknown survey status for 5 participants because of missing or invalid SSN.

The demographics of those in the biorepository pilot project were similar to those who were in the self-registration component of the Registry. Because the Biorepository participants are only taken from the self-registration component of the Registry, the differences in the demographics between those who self-registered and those identified from the Registry (administrative data plus self-registration data) also apply to those in the Biorepository. We will make sure to provide this information to researchers who request samples and will include this as a limitation in any publication initiated by ATSDR. In addition, ATSDR is working to increase minority participation in the self-registration portion of the Registry and the Biorepository.

B.4.Test of Procedures or Methods to be Undertaken

The web site has been tested and continues to be tested to assure its usability. No further procedures or methods are needed at this time for the Registry. The procedures and methods were tested as part of the pilot study. Details about the pilot study can be found in Attachment 14.

B.5. Individuals Consulted on Statistical Aspects and Individuals Collecting and/or Analyzing Data

Individuals consulted on statistical aspects:

Leah Bryan, MPH

Senior Statistician

Carter Consulting Corporation, Inc.

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-0953

Email: [email protected]

G. David Williamson, PhD

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-3669

Email: [email protected]

Ted Larson, MS

Epidemiologist

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-3695

Email: [email protected]

Lorene Nelson, PhD

Associate Profession

Division of Epidemiology

Department of Health Research & Policy

Stanford University School of Medicine

Pasteur Drive, Room T233

Stanford, CA 94305-5405

Phone: 650-723-6854

Email: [email protected]

Jaime Raymond, MPH

Data Manager

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-3627

Email: [email protected]

Person responsible for oversight, data collection, and analysis:

Paul Mehta, MD

Principal Investigator

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-0556

Email: [email protected]

Wendy E. Kaye, PhD

Point of Contact

ATSDR

4770 Buford Highway, MS F-57

Atlanta, GA 30341

Phone: 770-488-3696

Email: [email protected]

References

1. Kaye WE, Sanchez M, Wu J. Feasibility of creating a national ALS registry using administrative data in the United States. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:433–9. http://dx.doi.org/10.3109/2 1678421.2014.887119

2. Mehta P, Antao V, Kaye W, Sanchez M, Williamson D, Bryan L, Muravov M, Horton D. 2014. Prevalence of Amyotrophic Lateral Sclerosis – United States, 2010-2011. MMWR Surveillance Summary 63(No. SS-07);1-14.

3. Kaye WE, Wagner L, Wu R, Mehta P. Evaluating the completeness of the national ALS registry, United States. Amyotroph Lateral Scler Frontotemporal Degener 2018;19:112–7. CrossRef PubMed

4. Nelson LM, Topol B, Kaye W, et al. Estimation of the prevalence of amyotrophic lateral sclerosis in the United States using national administrative healthcare data from 2002 to 2004 and capture-recapture methodology. Neuroepidemiology 2018;51:149–57. CrossRef PubMed

5. Jordan H, Fagliano J, Rechtman L, Lefkowitz D, Kaye W. Population-based surveillance of amyotrophic lateral sclerosis in New Jersey, 2009–2011. Neuroepidemiology 2014;43:49–56. http://dx.doi. org/10.1159/000365850

6. Jordan H, Rechtman L, Wagner L, Kaye WE. Amyotrophic lateral sclerosis surveillance in Baltimore and Philadelphia. Muscle Nerve 2015;51:815–21. http://dx.doi.org/10.1002/mus.24488

7. Rechtman L, Wagner L, Kaye W, Villanacci J. Updated Prevalence and Demographic Characteristics for ALS Cases in Texas, 2009–2011. South Med J 2015;108:483–6.

8. Freer C, Hylton T, Jordan HM, Kaye WE, Singh S, Huang Y. Results of Florida’s Amyotrophic Lateral Sclerosis Surveillance Project, 2009–2011. BMJ Open 2015;5:e007359. http://dx.doi.org/10.1136/ bmjopen-2014-007359

9. Valle J, Roberts E, Paulukonis S, Collins N, English P, Kaye W. Epidemiology and surveillance of amyotrophic lateral sclerosis in two large metropolitan areas in California. Amyotroph Lateral Scler Frontotemporal Degener 2015;16:209–15. http://dx.doi.org/10.3109 /21678421.2015.1019516

10. Wagner L, Rechtman L, Jordan H, et al. State and metropolitan area-based amyotrophic lateral sclerosis (ALS) surveillance. Amyotroph Lateral Scler Frontotemporal Degener 2015;17:128–34. http://dx.doi.org/10. 3109/21678421.2015.1074699

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