Caregiver Outcomes of Alzheimer's Disease Screening
Phase: NA
Conditions: Alzheimer Disease
Sponsor: Indiana University

 
                                                                                                                                      
                                   
 
 
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Caregiver Outcomes of Alzheimer’s Disease Screening (COADS) Protocol 
NCT03300180 
5/12/2022 
 
 

 
                                                                                                                                      
                                   
 
 
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The Caregiver Outcomes of Alzheimer’s Disease Screening (COADS) 
Protocol 
 5.12.2022 
 
BACKGROUND AND STUDY AIMS 
The United States Preventive Services Task Force (USPSTF) stated, “Although the evidence on 
routine screening is insufficient, there may be important reasons to identify early cognitive 
impairment. This information may also be useful to patients and their caregivers and family 
members in anticipating and planning for future problems that may develop as a result of 
progression of cognitive impairment.” Currently, half of Americans with Alzheimer’s disease or a 
related dementia (AD) never receive a diagnosis. For those who do, the diagnosis often occurs 
two to five years after the onset of symptoms. A majority of people with AD receive care from 
their family. A delayed AD diagnosis may perpetuate family beliefs that changes in cognition are 
part of “normal aging” which have been shown to aggravate caregivers’ stress, burden, and 
sense of isolation. Furthermore, family members may not notice their own changing role, leaving 
them vulnerable or unprepared to become a caregiver.  
 
Early detection of AD from screening may enhance the family member’s transition to a caregiver 
by providing an opportunity for them to learn about the syndrome, receive interventions, and 
prepare for their caregiving role. Alternatively, early detection might trigger a process of role 
transition for the family member to a caregiver that evokes negative emotions or incurs social 
costs that are too high given the lack of a cure. The benefits and risks of AD screening for 
family members of older adults are unknown.  
 
We are proposing the first randomized controlled trial (RCT) to evaluate the benefits and harms 
of AD screening on family members of older adults. The proposed trial will randomize1,800 
dyad (older adult and family member) into three groups; Screen Only, Screen Plus and Control 
group, and will have 1,800 completed dyad baselines. 
 
Patients in the Screen Only and Screen Plus groups will be screened at baseline utilizing either 
the Mini-Cog (in-person recruitment) or MIS-T (phone recruitment).  During COVID 19 in person 
restrictions, we will use the MIS-T for every phone screen and add the clock draw portion of the 
mini-cog as a pass/fail measure to capture visual/spatial and executive function not found in the 
MIS-T alone if the patient is able. Information, in plain language, about how the patient 
performed on the screening will be disclosed in separate letters to the patient and to the family 
member. For patients who fail the screen, the patient and family members will also receive an 
infographic that visually represents the information in the letter regarding the screening test and 
brain health.  
 
 Patients and family members in the Screen Only group will also receive a resource guide 
with local clinical resources for memory specialists.  The Screening Plus group will not 
receive the resource guide but the family members in this group will receive two phone 
calls following receipt of the letter and infographic. The first call will be from the COADS 
PI (or their designee thanking them for being in the study and letting them they will be 

 
                                                                                                                                      
                                   
 
 
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receiving a phone call from a staff member at the Aging Brain Program (ABC) to answer 
any questions they may have and schedule a follow-up for diagnostic assessment.  
  This phone call will include an opportunity for the family to ask questions and have a 
conversation about the program and diagnostic evaluation and management. Follow-up 
diagnostic evaluation can occur at the Aging Brain Care Program or, if preferred in the 
patient’s home with trained personnel in an attempt to replicate the clinic visit.  Dyads 
will be offered transportation assistance if they chose the Aging Brain Care Program and 
are unable to get themselves there. If the visit occurs in the home, dyads will also be 
given the opportunity to have a post home visit meeting which can occur in the Aging 
Brain Care Program or at home. Dyads have the option to refuse the follow-up visit. The 
patient’s PCP is also be notified of the screening results. 
 
In both the Screen Only and Screen Plus groups, the patient’s PCP will be notified, through the 
patient’s EHR, that the patient is participating in this study and a statement, in plain language, 
about how they performed on the screening test.  
 
The Control group patients will not be screened at baseline therefore patients and family 
members will not receive a letter or infographic.  Control group patients will be observed through 
surveillance of their EHR for any screening or incident AD diagnoses that occur as part of 
routine care for 24 months.  At the last follow-up assessment (24 months), we will screen 
patients in the control group and conduct an interview with the family member to detect possible 
cognitive impairment. 
 
 
Specific Aim 1: Evaluate the impact of AD screening on family members’ quality of life. 
Hypothesis 1: In comparison to the control group, family members randomized to the Screen 
Only or the Screen Plus groups will express higher levels of health-related quality of life at 24 
months as measured by the Short Form Health Survey (SF-36). 
 
Specific Aim 2: Evaluate the impact of AD screening on family members’ mood and anxiety. 
Hypothesis 2: In comparison to the control group, family members randomized to the Screen 
Only or the Screen Plus groups will express lower rates of depressive symptoms and anxiety at 
24 months as measured by the Patient Health Questionnaire (PHQ-9) and the Generalized 
Anxiety Disorder Scale (GAD-7). 
 
Specific Aim 3: Assess the impact of AD screening on family members’ caregiving 
preparedness and caregiving self-efficacy. 
Hypothesis 3: In comparison to the control group, family members randomized to the Screen 
Only or the Screen Plus group, will be more prepared for caregiving and have higher self-
efficacy at 24 months as measured by the Preparedness for Caregiving Scale and the Revised 
Scale for Caregiving Self-Efficacy. 
 
Specific Aim 4: Compare the effectiveness of two strategies for diagnostic evaluation and 
management after AD screening.  
Hypothesis 4: In comparison to the Screen Only group, family members randomized to the 
Screen Plus group will express higher levels of health-related quality of life, caregiver 
preparedness and caregiving self-efficacy and lower levels of depressive and anxiety symptoms 

 
                                                                                                                                      
                                   
 
 
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at 24 months, as measured by the SF-36, Preparedness for Caregiving Scale, the Revised 
Scale for Caregiving Self-Efficacy, PHQ-9, and GAD-7, respectively. 
 
 
 
 
METHODS 
 
Study Design 
 
 Three arm, blinded, randomized controlled trial 
 
 1,900 patient-family member dyads from primary care clinics in central Indiana (n=3800) 
 
 1800 completed baselines; 600 dyads randomized to each of the three study arms 
 
 
 Screen Only group: Patients will receive screening for AD (n=600). Patient and family 
members will receive a letter about how the patient performed on the screening. If they 
screen positive (e.g. ≤5 on the MIS-T or clock draw pass/fail with the MIS-T) the patient 
and family member will receive an infographic and some information about local clinical 
resources for them to peruse regarding follow-up care. The patient’s PCP will also be 
notified of the screening results. Additionally, at the 24 month follow up, family members 
will be asked to complete the IQCODE to detect possible cognitive impairment in the 
participant  
 
 Screen Plus group: Patients will receive screening for AD (n=600). Patient and family 
members will receive a letter about how the patient performed on the screening. If they 
screen positive (e.g. ≤5 on the MIS-T and clock draw pass/fail with the MIS-T), the 
patient and family member will receive an infographic. Also, the family member will 
receive two follow-up phone calls. One from the COADS Study PI (or their designee) 
and one from a staff member at the Aging Brain Care Program (ABC). This phone call 
will include an opportunity for the family to ask questions and have a conversation about 
the program and diagnostic evaluation and management. Follow-up diagnostic 
evaluation can occur at the Aging Brain Care Program or, if preferred in the patient’s 
home with trained personnel in an attempt to replicate the clinic visit.  Dyads will be 
offered transportation assistance if they chose the Aging Brain Care Program and are 
unable to get themselves there. If the visit occurs in the home, dyads will also be given 
the opportunity to have a post home visit meeting which can occur in the Aging Brain 
Care Program or at home. Dyads have the option to refuse the follow-up visit. The 
patient’s PCP will also be notified of the screening results. Additionally, at the 24 month 
follow up, family members will be asked to complete the IQCODE to detect possible 
cognitive impairment in the participant  
 
 Control group: Patients will receive no AD screening (n=600 dyads) at baseline. At the 
24-month follow-up, patients will complete the Cognitive Change Index (CCI) and an 
interview with the family member will be completed to detect possible cognitive 
impairment. 

 
                                                                                                                                      
                                   
 
 
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Participants 
 Patients will be adults 65 years or older; 
 Have no prevalent diagnosis of Alzheimer’s disease or related dementia and not 
previously screened for AD as part of a research study. 
 Family members will be 21 years or older and identified by the patient as the person who 
would most likely assist with activities of daily living and/or medical decision making if 
the patient needed assistance. 
 See Table 1 for patient and caregiver inclusion and exclusion criteria 
 
Recruitment Sites (as of 9/17/18): 
 Indiana University Health Primary Care Practices  
 Eskenazi Health Primary Care Practices  
 
Primary outcome: Family member quality of life at 24 months. 
Co-Primary outcomes: Family member depressive symptoms and family member anxiety at 24 
months. 
Co-Secondary outcomes: Family member caregiving preparedness and caregiving self-efficacy 
at 24 months. 
Exploratory outcome: Comparison of all outcomes (noted above) between the family members 
in Screen Only vs. Screen Plus groups. 
Table 1. Inclusion and exclusion criteria for the proposed trial 
Inclusion Criteria 
Patients 
Family Members 
65 years or older 
21 years of older 
At least one visit to primary care practice within past 24 
months  
Lives with the patient or lives within a 50 mile radius 
Ability to provide informed consent 
Ability to provide informed consent 
Ability to communicate in English 
Ability to communicate in English 
 
Identified by patient as the person most likely to provide them 
care if needed 
Exclusion Criteria 
Patients 
Family Members 
Has a diagnosis of AD as determined by ICD-10 code 
Is a non-family member who is not a legal Healthcare Power of 
Attorney 
Evidence of a prescription for a cholinesterase inhibitors or 
memantine 
Has a serious mental illness such as bipolar or schizophrenia 
as determined by ICD-10 code 
Has a serious mental illness such as bipolar or schizophrenia 
as determined by ICD-10 code 
Permanent resident of a nursing facility 
Has a diagnosis of AD as determined by ICD-10 code 
Is already enrolled in HABC programs 
 

 
                                                                                                                                      
                                   
 
 
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Table 2. Measures 
Outcomes 
Construct/Core 
Attributes 
Outcome 
measure(s) 
Name of 
Measure  
Description 
Scoring 
When 
Source 
Primary 
outcome 
Family 
member 
Quality of Life 
 
 
 
Quality of Life 
Medical 
Outcomes 
Study Short 
Form Health 
Survey 36 
(SF-36) 
36-items that 
measure health-
related quality of 
life, mental, 
physical, and 
social functioning 
Scores range 
0-100; 
Higher 
scores more 
QOL 
Baseline 
6 mos. 
12 mos. 
18 mos. 
24 mos. 
Family 
reported  
 
 
Patient 
reported 
Secondary 
outcomes 
Family 
member  
Mood 
Depressive 
symptoms 
 
The Patient 
Health 
Questionnaire
-9 (PHQ-9) 
9-item measures 
of depressive 
symptoms.  
Depression 
Severity: 0-4 
none, 5-
9 mild, 10-14 
moderate, 
15-19 
moderately 
severe, 20-
27 severe.  
B 
6 
12 
18 
24 
Family 
reported  
 
 
Patient 
reported 
Anxiety 
Generalized 
Anxiety 
Disorder 
Scale-7 (GAD-
7) 
7-item measure of 
anxiety 
GAD-
7 total score 
for the seven 
items ranges 
from 0 to 
21. Scores of 
5, 10, and 15 
represent cut 
points for 
mild, 
moderate, 
and severe 
anxiety. 
B 
6 
12 
18 
24 
Family 
reported  
 
Patient 
reported 
Caregiver 
preparedness 
 
Caregiver 
preparedness 
 
Caregiver 
Preparedness 
Scale 
8-item measure 
with 1 open-
ended question. 
Self-rated 
instrument that 
consists of eight 
items that asks 
caregivers how 
well prepared they 
believe they are 
for multiple 
domains of 
caregiving. 
Responses are 
rated on a 5-point 
scale with scores 
ranging from 0 
(not at all 
prepared) to 4 
(very well 
prepared).  
The scale is 
scored by 
calculating 
the mean of 
all items 
answered 
with a score 
range of 0 to 
4. The higher 
the score the 
more 
prepared the 
caregiver 
feels for 
caregiving 
B 
6 
12 
18 
24 
Family 
reported  
Caregiving 
self-efficacy 
Caregiving 
self-efficacy 
The Revised 
Scale for 
Caregiver Self 
Efficacy 
15 item measure 
with three 
domains of 
caregiving self-
efficacy: 
Obtaining 
Use of a total 
score 
reflecting the 
sum of all 15 
items is 
contrary to 
B 
6 
12 
18 
24 
Family 
reported  

 
                                                                                                                                      
                                   
 
 
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Respite, 
Responding to 
Disruptive Patient 
Behaviors, and 
Controlling 
Upsetting 
Thoughts 
the view of 
self-efficacy 
as domain 
specific and 
can mask 
significant 
relationships 
between 
subscales 
and other 
constructs. 
For these 
reasons, we 
strongly 
advocate 
using scores 
for the three 
subscales 
rather than a 
total score. 
Other 
measures 
Socio-
demographics 
Socio-
demographics 
COADS 
Created 
Questionnaire to 
measure items 
such as 
relationship to the 
patient/family, 
frequency and 
type of contact 
with the patient, 
geographic 
distance from the 
patient, education 
level, annual 
income, self-
reported health 
status, etc. 
Co-variates 
B 
Family 
reported  
 
Patient 
reported 
Cognitive 
impairment  
Cognitive 
impairment 
Mini-Cog 
For in-person 
recruitment we will 
use the Mini-Cog 
which is a 3 
minute test of 
cognition 
including a clock 
draw and 3 word 
recall  
Score ranges 
from 0-5. 
0=impairmen
t;1-2 
abnormal 
clock draw 
then positive 
for cognitive 
impairment; 
1-2 Normal 
clock draw 
then 
negative for 
cognitive 
impairment; 
3 negative 
screen  
B 
(patients 
randomiz
ed to 
screenin
g only) 
Patient 
reported 
MIS-T 
The MIS-T is 
comprised of four-
items with 
semantic cues to 
assess episodic 
memory 
performance; a 
cut-point of 5 or 
less was used to 
classify those with 
potential memory 
impairment 
6+ not 
impaired 
 
<=5 impaired 
B 
(patients 
randomiz
ed to 
screenin
g only) 
Patient 
reported 

 
                                                                                                                                      
                                   
 
 
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Cognitive 
Change Index 
(CCI-20-s) 
The Cognitive 
Change Index 
(CCI) is a tool 
used to assess 
the perception of 
cognitive decline 
in memory, 
executive 
function, and 
language domains 
from both self and 
informant 
perspectives. 
 
24 month 
Patient 
Reported 
 
IQ CODE 
16-item measure 
of the patient’s 
changes in 
cognition and 
function as 
reported by the 
family  
Sum each 
question and 
divide by the 
number of 
questions 
(16). The 
result is 
a score that 
ranges from 
1 to 5. An 
average scor
e of 3 means 
that the 
subject is 
rated as 'no 
change'. 
A score of 4 
means 'a bit 
worse', and 
a score of 5 
is 'much 
worse'. 
24 
months 
Family 
reported 
 
Knowledge of 
patient being 
screened for 
AD 
COADS 
Created 
2-items to assess 
if family members 
are aware if the 
patient has been 
screened in the 
study and about 
their performance 
Yes or no 
6 
12 
18 
24 
Family 
reported 
 
Evidence of 
screening for 
AD or new 
diagnoses of 
AD 
COADS 
Created 
EHR diagnosis  
Yes or no 
B 
6 
12 
18 
24 
EHR 
 
 
Caregiver 
burden 
Oberst 
Caregiving 
Burden Scale 
15-item 
questionnaire that 
rates 15 different 
types of 
caregiving tasks 
based on 
perceived time 
and difficulty 
(Each item is 
scored on a 5-
point response 
scale.  
 
B 
12 
24 
Family 
reported 
 
 
COADS 
Loneliness 
Assessment 
for patient and 
caregiver 
PROMIS NIH 
Toolbox 
Loneliness 
(Ages 18+)-
Fixed Form 
5-item 
questionnaire to 
assess loneliness 
on a scale from 1-
5 
 
B 
6 
12 
18 
24 
Family 
reported 
 
Patient 
reported 
 
 
COADS 
COVID  
NIH Toolbox 
11-items to 
assess COVID-19 
 
B 
6 
 

 
                                                                                                                                      
                                   
 
 
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impact and 
experience 
(Asked after the 
PHQ-9 and GAD-
7) 
12 
18 
24 
 
 
Economic 
Impact ? 
Health 
Motivation 
Scale 
8-item 
questionnaire to 
assess health 
motivation 
All response 
are on a 7 
point Likert 
Scale of  (7) 
strongly 
agree, (1) 
strongly 
disagree 
24 
Family 
reported 
 
 
Economic 
Impact? 
Motivation to 
Change 
Lifestyle and 
Health 
Behaviors for 
Dementia Risk 
Reduction 
(MCLHB-
DRR) Scale 
11-item 
assessment with 
5 section about 
perceieved 
benefits, cues to 
action, general 
health motivation 
and self-efficacy 
All response 
are on a 5 
point Likert 
Scale of (5) 
strongly 
agree, (1) 
strongly 
disagree 
24 
Family 
reported 
 
 
Economic 
Impact 
Resource 
Utilization in 
Dementia 
(RUD) 
Instrument 
 
 
24 
Family 
reported 
 
 
Intervention Description and Timing of Measures 
Participants will be recruited from primary care offices affiliated with Eskenazi Health and IU 
Health.  
 
Step 1: Identification of Potential Participants 
 Participants will be identified in a variety of ways and will be tailored based on the 
recruitment site. Patients will be identified via the Indiana Network for Patient Care, 
(INPC) which can access patient lists by doctor, clinic, and PC clinic schedules.  
Physicians will be notified first of their patients’ potential eligibility and be asked if the 
COADS study personnel may approach the patient and their family member for 
participation. Physicians are routinely given 2 weeks to review the list of their potentially 
eligible patients (per IU PBRN). Physicians will be given the opportunity to opt-out of 
study participation at this time. Following either approval from the PCPs, or at the end of 
the two-week review period study personnel will mail out an introductory letter, email or 
post card to patients. Study personnel with then approach patients via telephone, email 
or in person in the-clinic to confirm eligibility and obtain informed consent.  
 
 We will consider any man or woman 65 years or older who has not been diagnosed with 
AD or related dementia, and is considered an active patient (PCP visit in- person or 
virtual within 24 months including requests for prescription refills, or questions and is 
able to provide consent, and speaks English. 
 

 
                                                                                                                                      
                                   
 
 
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 We will approach the primary family member/caregiver/informant for each eligible 
participant.  Family members will be eligible if they are patient-identified or self-identified 
as a person who is likely to provide care for the patient, is 21 years or older, lives within 
a 50-mile radius of the participant, is able to consent, and speaks English 
 
 Rolling enrollment will take place over 36 months with an average monthly recruitment of 
50 dyads 
 
Step 2: Enrollment 
 Following eligibility determination and the informed consent process (including HIPAA 
release), dyads will be randomly assigned to one of three groups, stratified by site (e.g. 
Eskenazi or IUH). Dyads are officially enrolled at this point.  
 
 Screen Only: at baseline, the study personnel will administer the mini cog or clock draw 
and MIS-T to the patient. During COVID 19 restrictions, we are able to use phone 
recruitment only, if the participant is able, we will administer the clock draw aspect of the 
Mini-Cog or the mini-cog in person if applicable to capture the executive and visual 
spatial aspects of this test. 
 
Dyads will then receive a letter with information about the patient’s AD screening results, 
provided in plain language. For patients who score ≥6 on the MIS-T and the clock draw 
as a pass/fail measure, the patient and family member will both receive a letter and 
infographic indicating the patient’s screening outcome results do not indicate signs of 
cognitive impairment. In cases where the patient scored ≤5 on the MIS-T and pass/fail 
on the clock draw or positive mini-cog screen, the patient and family member will both 
receive a letter indicating the patient scored lower than expected. The letter will 
encourage the patient and family member to discuss the results with the patient’s PCP at 
the earliest possible time. The dyad will also receive a resource guide with local clinical 
sources with memory specialists.  At the 24 month assessment Informant Questionnaire 
on Cognitive Decline in the Elderly (IQCODE) will be administered to the family 
member.  The patient’s PCP is also notified of the screening results. 
 
 Screen Plus: As described above, research assistants will screen patients with the MIS-
T. and pass/fail on the clock draw or the mini-cog if possible.  Patients, who score ≥6 on 
the MIS-T and pass/fail on the clock draw) or mini-cog if possible, will receive a letter 
and infographic. If the patient scores ≤5 on the MIS-T or ≤2 and a  pass/fail on the clock 
draw or the mini-cog if possible , the phone call and letter to the dyad will indicate that 
they will be receiving a follow-up call from the ABC Program (letter includes ABC contact 
name who will be calling and phone information). At the 24 month assessment, the 
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) will be 
administered to the family member.  The patient’s PCP is also notified of the screening 
results.  
 
 
 Control Group (No screen, surveillance group) Patients will not be screened for 
cognitive function at baseline. Similar to the design of cancer screening trials, this group 

 
                                                                                                                                      
                                   
 
 
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will undergo active surveillance throughout the study via EHR to monitor any AD 
screening, new diagnoses of AD, and/or new prescriptions for anti-dementia 
medications. At the 24-month outcome assessment, study personnel will administer the 
Short Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to the 
family member and the patient will complete the Cognitive Change Index (CCI).  
 
 
 Rolling enrollment will take place over 36 months with an average monthly enrollment of 
50 dyads. The proposed trial will reduce loss to follow-up for longitudinal assessments 
by engaging the dyads every 6 months throughout the study (6, 12, 18, and 24 months). 
This includes keeping the assignment of research staff and participants consistent at 
each outcome assessment, sending reminder letters before each assessment, and 
sending birthday cards signed by the study team. This strategy has produced a <1% loss 
to follow-up in the pilot study.   
 
Statistical Plan 
Overview 
Our study is a three-arm RCT to determine the impact of AD screening on older adults’ family 
members. By design, it will also test the congruence of outcomes between the patient and 
family member. The 1:1:1 randomization creates three randomized groups. 
 
 For analysis, we will first examine univariate distributions of continuous variables in order 
to detect any potential violations of assumptions to our planned parametric methods of 
analyses.  
 
 Variables will be transformed as needed to ensure normal distribution assumptions are 
met.  
 
 We will use nonparametric methods if transformations are inadequate.  
 
 Demographic characteristics will be compared among the groups in order to evaluate 
whether the randomization effectively balance the dyads.  
 
 We will use Chi-squared tests or Fisher’s exact tests to compare the frequencies of 
categorical variables. Analysis of variance (ANOVA) or its nonparametric alternative, the 
Wilcoxon rank sum test, will be used to compare the distribution of continuous variables 
among the groups.  
 
 All analyses will be conducted using SAS 9.4 (SAS Institute, Carey, North Carolina). 
 
 
Primary Aim 
 

 
                                                                                                                                      
                                   
 
 
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 Multi-level mixed effects models will be used to examine differences in SF-36 scores 
for both patients and family members using dyadic analytic approaches. For this aim, we 
will compare family members in the two screening groups (Screen Only and Screen 
Plus) to those in the no screening (Control) group. Repeated SF-36 scores from both 
patients and family members will be included as the outcome variables with participant 
type (patient or family member), group (Screening Only and Screening Plus versus 
Control), time, and interaction between groups and time as independent variables. We 
will use a multi-level variance-covariance matrix in the mixed effects models to account 
for two sources of potential correlations. Correlations from measures obtained from the 
same individual over time, an autoregressive correlation will be used. Correlations within 
a dyad between a patient and his/her family member. A compound symmetry structure 
will be used for the within-dyad correlation. Parameter estimation and hypothesis tests 
for the mixed-effects models will be conducted using the maximum likelihood approach 
that provides robust estimation under the missing at random mechanisms. 
 
 A significant interaction between group and time would indicate differences in changes 
of SF-36 over time between the two screening groups compared to the no screening 
group. Absence of significant interactions, significant main group effects will suggest 
differences in SF-36 between groups’ at all follow-up times. For Hypothesis 1 we will use 
a linear contrast for SF-36 from family members in the combined screening groups 
(Screen Only and Screen Plus) versus the no screening (Control) group at 24 months. 
We will also include additional covariates in the mixed effects models to determine 
whether family member characteristics (relationship to patient, frequency or types of 
contact, etc.) and knowledge of screening are associated with the outcome measures.  
 
 The multi-level mixed effects models provide a powerful modeling framework for 
analyzing dyadic outcomes. An alternative model using family member outcomes as the 
dependent variable and patient outcomes as an independent variable would 
underestimate variances in outcome measures by ignoring the randomness in the 
patients’ outcomes by treating patient outcomes as fixed covariates. In our proposed 
models, correlations between patients and their family members on outcome measures 
(congruence) are explicitly included in the mixed effects models and estimated using 
maximum likelihood approach. The inclusion of the additional covariance structure due 
to repeated measures and within dyad correlation also makes it possible to estimate 
potential differences in patient-family member congruence over time. Comparisons on 
patient-family member congruence among the groups will be conducted using the 
likelihood ratio test (LRT) derived from a mixed effects model using group specific 
correlation structure versus a model using the same correlation in all groups. Changes in 
congruence can also be conducted using LRT comparing a mixed effects model with 
time specific correlation structure versus a model using equal correlations across time. 
By re-aligning data from the family member at specific lag time behind measures from 
patients, we will also be able to detect a lag effect in family member outcomes using this 
modeling framework. 
 
 
Secondary Aim  
 

 
                                                                                                                                      
                                   
 
 
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 Separate mixed effects models with PHQ-9 or GAD-7 scores collected at baseline, 6, 
12, 18 and 24 months from both patients and family members will be used as the 
outcome variables for Specific Aim 2. Participant type, randomized group (Screen Only 
and Screen Plus versus no screening), time and interaction between group and time will 
be used as independent variables, similarly to the modeling procedures described in 
details for Aim 1 above. Linear contrasts will be used to compare PHQ-9 and GAD-7 
scores from family members in the combined screening groups versus the no screening 
group at 24 months. Dyad congruence in PHQ-9 and GAD-9 will be examined using 
LRT from the mixed effects models following the procedure described for Aim 1.   
 
Secondary Aim  
 
 Mixed effects models with Caregiver Preparedness Scale or the Revised Scale for 
Caregiver Self-Efficacy scores collected at baseline, 6, 12, 18 and 24 months will be 
used as the outcome variables, group (Screen Only and Screen Plus versus Control), 
time and interaction between group and time as independent variables. Linear contrasts 
will be used to compare preparedness and caregiver self-efficacy scores in the 
combined screening groups versus the no screening group at 24 months. We will also 
evaluate potential interactions between patient’s/family member characteristics and 
variables associated with increased level of caregiver preparedness and self-efficacy 
over time. 
 
 
Secondary Aim  
 
 To measure the impact and compare strategies for evaluation and treatment post 
screening, we will compare quality of life measures, caregiver preparedness, 
caregiving self-efficacy, depression and anxiety symptoms from family members 
in the Screen Only (notify dyad and PCP of results only) group to the Screen Plus (notify 
dyad and PCP and a referral to ABC Program if screen positive) group using multi-level 
mixed effects models, similarly to the approach described in details for Aim 1. Separate 
mixed effects models with SF-36, Caregiver Preparedness Scale, Revised Scale for 
Caregiver Self-Efficacy, PHQ-9 or GAD-7 scores collected at baseline, 6, 12, 18, and 24 
months from family members will be used as the outcome variables. Screening group 
(Screening Only versus Screening Plus), time and interaction between group and time 
will be used as independent variables. Linear contrasts will be used to compare all scale 
scores between the two screening groups at 24 months.  
 
 
 
Sensitivity analyses for the impact of refusals and other sources of missing data  
 
 We will compare patient and family member characteristics between those who 
complete at least one or more follow-up assessment(s) after baseline and those who did 
not complete any assessment beyond baseline due to refusal or other reasons. 
Significant variables detected from these comparisons will be included in the mixed 
effects models for the primary and secondary outcomes as covariates to control for 
potential bias from those missing follow-up outcomes. Under the missing at random 

 
                                                                                                                                      
                                   
 
 
14 | P a g e  
 
assumption, results from the mixed effects models will remain unbiased if the variables 
contributing to the missing data are included as covariates in the models. We will also 
perform additional sensitivity analyses to examine whether the missing at random 
assumption using the selection model approach under an informative missing 
mechanism impacts our analyses. 
 
 
Statistical Power 
 
Sample Size and Power Considerations for COADS 
For the models in Aims 1, 2 and 3, we assume a base correlation of 0.2  and a decay rate of 0.8 
in a linear exponent autoregressive correlation structure for repeated measures and a 
continuous time response, we will need to have 540 dyads per group to have complete data at 
24 month in order to achieve 82.6% power to detect a group by time interaction with an effect 
size of 0.24 SD with higher SF-36, lower PHQ-9, GAD-7, higher caregiver preparedness and 
self-efficacy scores at 24 months in the combined screening groups (Screen Only and Screen  
Plus) compared to family members in the no screening (Control) group. Our previous screening 
studies and studies in primary care had a 5% loss to follow-up (death or withdraw) within a 12-
month period. Therefore, allowing a loss to follow-up rate of 10% over the 24 months, we plan to 
enroll 600 dyads per group into this study. For Aim 4, using similar assumptions on the 
correlation structure for repeated measures and also 10% attrition rate, we will have 83.4% 
power to detect a significant group and time interaction with an effect size of 0.28 SD comparing 
family members randomized to the screening plus group to those in the screening only group at 
24 months. Power estimation was conducted using the GLM Power procedure in SAS.  
 
 
Timeline 
Table 3. Study Timeline 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Hire/ train staff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revise protocol manual and 
database 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB modification and approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject recruitment and consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data collection  
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepare abstracts and 
manuscripts 
 
 
 
 
 
 
 
 
Disseminate results