A Patient Advocate to Improve Real-world Asthma Management for Inner City Adults
Phase: NA
Conditions: Asthma, Communication
Sponsor: University of Pennsylvania

TITLE: A Patient Advocate to improve real-world asthma management for adults living in the inner-city   
 
  
  
 
 

A. SPECIFIC AIMS   
Asthma, a chronic treatable disease, affects 17.5 million US adults. Blacks have 3.3 times the emergency 
department (ED) visits, 2.2 times the hospitalizations, and 2 times the death rate for asthma compared to 
whites. Other groups including Puerto Ricans also have increased morbidity. Few interventions have targeted 
low-income minority adults with moderate or severe asthma and even fewer have focused on the real-world 
clinical practices where care is provided. Yet, according to an Institute of Medicine report, access to health 
care and patient-provider communication may be particularly difficult to achieve for low-income and minority 
patients and contribute to health disparities.1 We propose to assess the effectiveness, sustainability, and 
budget impact of a patient navigator intervention to facilitate and maintain patient-provider communication and 
access to chronic care of moderate or severe asthma in low income minority adults with other chronic 
morbidities. We will implement the intervention in a variety of clinic practices including those of an urban 
academic health center, a VA, and a federally qualified health center and in both English-speaking and 
Spanish-speaking patients. Our intervention is tailored to patients and their clinics, allowing the clinic practice 
to take account of individual patients’ comorbidities and psychosocial and community barriers to accessing 
care. Informed by focus groups of patients and providers, our intervention activates both groups. It integrates 
activities with demonstrated efficacy; its feasibility, acceptability, and preliminary efficacy were demonstrated in 
RC1 HL099612 (HAP Study). Here we test its effectiveness, sustainability, and applicability to the real world.  
Our navigator, called a Patient Advocate (PA), according to the preference of patients in the focus groups, 
works with patients by coaching and modeling preparation for a visit with the asthma doctor, attending the visit 
with the permission of participant and provider, and confirming understanding of issues discussed. The PA also 
facilitates scheduling, obtaining insurance coverage, overcoming patients’ unique social and administrative 
barriers to carrying out medical advice, and exchange of information between providers and patients. PA 
activities are individualized, multi-faceted, take account of comorbidities, and are generalizable to other chronic 
diseases. The PAs, highly valued by patients in RC1HL099612, are recent college graduates interested in 
health-related or education careers, research experience, working with patients, and generally have the same 
race/ethnicity distribution as potential subjects. 
This dissemination and implementation project refines the intervention of RC1 HL099612 for real-world 
practice by 1) conducting a randomized controlled trial that compares the Patient Advocate Intervention 
(PAI) to currently practiced guideline-based usual care; 2) carrying out the intervention in a variety of primary 
care and asthma specialty practices; 3) extending the observation time to a year to test its sustainability; 4) 
assessing patient-centered outcomes including asthma control, quality of life, ED visits, and hospitalizations; 5) 
assessing mediators/moderators of the PAI-asthma outcome relationship; and 6) evaluating its cost-
effectiveness.   
Aims: 
Recruiting 300 adults with moderate or severe persistent asthma from clinics serving low-income, urban, 
primarily minority patients, we will conduct a randomized controlled trial (RCT) to:   
Specific Aim 1: Assess whether 6 months of the PAI improves asthma control relative to baseline compared 
with usual care (UC) and whether such a difference is sustained in the 6 months following the intervention’s 
completion. 
Specific Aim 2: Assess whether the PAI improves other asthma outcomes (need for prednisone bursts, ED 
visits, hospitalizations, quality of life, FEV1) relative to baseline compared with UC at 6 months and is 
sustained in the 6 months following the intervention’s completion. 
Secondary Aim 1: Evaluate whether improvement in self-efficacy, appointment-keeping, communication 
with providers, adherence, and navigating ability mediate the effect of the PAI on asthma control. 
Secondary Aim 2: Assess whether baseline patient factors (e.g., educational attainment and health 
literacy, demographics, household income, depression, anxiety, social/community barriers) and provider 
factors (e.g. demographics, years in practice, primary versus specialty practice), moderate the effect of the PAI 
on the mediators and asthma control. 
Specific Aim 3: Measure the incremental direct and indirect (i.e., productivity) costs of the PAI compared with 
UC from both payer and societal perspectives and determine the incremental cost-effectiveness of the PAI 
relative to UC for asthma control and other outcomes. 
Exploratory Aim: Conduct post-study focus groups of providers to explore awareness of the intervention and 
response to the PA.  
Impact: This proposal is innovative and significant because it 1) compares effectiveness of PA to usual care, 
2) focuses on inner-city low-income predominantly minority adults who experience high asthma morbidity, 3) 
uses a real-world behavioral intervention to test for sustainability in an RCT design, 4) tests a multi-faceted 
individualized intervention which considers comorbidities as it provides a model of chronic asthma 
management and is thus generalizable to patients with other chronic diseases and comorbidities, 5) examines 
patient-provider communication, 6) uses a unique PA, 7) considers both English- and Spanish-speaking 
patients, and 8) assesses the cost-effectiveness of PAI relative to UC. 

Interface
Health Policies
•Regulations at State & Federal Levels
Insurance Status
Reimbursement Levels
Operation of the Health System
•Cultural Sensitivity
•Work Force Diversity
•Use of Evidence-Based Care
Provider/Clinician Factors
•Stereotyping, attitudes of minority groups
•Clinician’s training
•Prescription Practices
•Diagnosis of Severity
•Provider/Patient Interaction
Social/Environmental Context
•Poverty
•Indoor/Outdoor Allergens
•Pollution
•Environmental Stress
Process of Care
•Access to treatment 
•Quality of Care
Differential Treatment/ Outcomes
•Prevalence
•Asthma control
•Quality of life
•# ED and Hospitalization
Health Care System
Individual/Community System
Legal, Economic, and Socio-cultural Parameters
Individual/Family Context
Inherent factors
•Genetics & biological factors
•Race/ethnicity
Modifiable factors
•Beliefs
•Health literacy
•Illness Management
= points where PA 
could potentially facilitate 
access to care or
help the provider &     
practice  take into account 
contextual information
Figure 1. Multilevel asthma disparities model by Canino et al 6
B. SIGNIFICANCE 
B.1. Asthma, a chronic treatable disease affecting 17.5 million US adults, is characterized by 
persistent disparity in prevalence, severity, and morbidity.2-6 Blacks have 3.3 times the ED visits, 2.2 times 
the hospitalizations, and 2 times the death rate for asthma compared to whites.2 Puerto Rican populations also 
have high morbidity.2, 7 The Institute of Medicine (IOM) found racial and ethnic inequities in health care at two 
levels: 1) the operation of the practice/health system where administrative tasks are completed; and 2) the 
individual patient-provider interaction.1  Asthma provides an excellent setting for addressing both levels. At the 
practice/health system level features associated with lower quality of asthma care in vulnerable patients 
include complicated office schedules, insurance, and health forms; lack of evening and urgent visit schedules; 
and absence of policies that 
consider cultural or language 
differences between patients 
and staff.8-10 At the patient-
provider level, physicians have 
been found to underestimate 
asthma severity in black 
patients.11 A PA can address 
both levels in a feasible real-
world approach. 
B.2. Canino et al4 
expanded upon the IOM 
levels, creating a multi-level 
framework that informs 
research and practice (Fig. 
1). Our PA coaches and 
models preparation for a visit 
with the asthma doctor, 
attending the visit with the 
permission of participant and 
provider, and confirming 
understanding of issues 
discussed. The PA facilitates 
scheduling, obtaining 
insurance coverage, overcoming patients’ unique social and administrative barriers to carrying out medical 
advice, and exchange of information between providers and patients including consideration of patients’ 
environmental and social context. The PAI is individualized, addressing relevant levels of the framework as 
indicated in Figure 1. Because the PA is a college graduate but not medically trained, PA activities can be 
distributed within one practice or several for those patients in most need.  
B.3. Communication, essential for improving health outcomes and eliminating health disparities, is 
compromised by language and cultural differences.1, 4, 12 In addition, accessing care, obtaining 
insurance, making appointments, and filling forms requires significant literacy. However, half of US 
adults have no more than basic reading and numerical skills.13 Health literacy is the subset of literacy skills 
necessary “to obtain, process and understand basic health information and services needed to make 
appropriate health decisions”,14 that is, to successfully self-manage a chronic disease like asthma.14-16 It 
includes cultural knowledge, reading comprehension, numerical skills, listening and speaking fluency.14 Low 
health literacy is found in all patient groups; its prevalence is increased among the poor and underserved 
minorities and is associated with poorer health access and outcomes, higher health costs, and less patient 
satisfaction with health providers.14, 15, 17-28 Low literacy may impair communication, self-efficacy, and ability to 
navigate the health system.29-31 In fact, there is concern that the literacy requirements to enroll in health plans 
under the Patient Protection and Affordable Care Act will impede enrollment by the very groups most in need 
of its provisions.32 A PA can address health literacy and cultural context, mitigating health disparities.29-31 
In asthma, low reading ability has been associated with improper use of inhalers and less asthma 
knowledge,33 poor aural skills with poorer disease management.34 However, inadequate health literacy is not 
associated with difficulty learning or retaining instructions about medications or inhaler technique,35 but rather 
reflects limited access to effective education.36 Limited literacy is not easily recognized because patients do not 
disclose such difficulty.37-39 Screening patients for low literacy may not measure the skills needed for accessing 
care, but may increase patient anxiety and deter communication.40 Thus, health literacy experts recommend 
providing the simplest explanation for all patients, tailoring formats to the individual patient, and confirming 
understanding using techniques such as “teach-back”(The patient teaches the instructions).41-43 Our PA 
promotes practical, immediate and sustainable communication using these methods.   
B.4. Inner-city low-income neighborhoods have been called “socially toxic,”44-46 because the 
presence of poverty, deprivation, disadvantage, and segregation results in increased exposure to indoor and 

outdoor pollutants, inadequate housing, tobacco, and violence. Exposure to violence has been associated with 
asthma symptoms in children and may be a marker of these toxic exposures.47-52 The disproportionate 
psychological stress of living in such communities may explain why interventions at the patient or practice level 
may not lead to results. Clinicians must understand these stresses and the community resources available to 
patients. The PA can promote this awareness.  
B.5. Patient Navigator activities are efficacious and inform our Patient Advocate Intervention (PAI). 
Harold P. Freeman, MD proposed the concept of a Patient Navigator (PN) to overcome barriers to early 
diagnosis and treatment of cancer of patients living in poverty in Harlem.53-55 In 2005 the National Cancer 
Center to Reduce Cancer Health Disparities adapted his PN (http://crchd.cancer.gov/pnp/pnrp-index.html). PN-
related interventions have focused on uninsured, minority, elderly, and low-income patients in a number of 
different settings, particularly in screening or assisting with induction of therapy for cancer.56-58 PNs have 
arranged transportation, scheduled appointments, ensured medical record availability, and provided social and 
financial support.59 PNs have demonstrated efficacy in activities that our PA will accomplish: coordination of 
care, navigation of the practice, increasing self-efficacy, and facilitating adherence.56, 60-68 PNs have enhanced 
communication, fostered trust, and improved patient satisfaction.64, 69, 70 Interventions that are PN-like also 
have demonstrated efficacy. Older outpatients accompanied by visit companions who facilitated visit 
communication at routine medical encounters were more satisfied with their physician.71 A tailored intervention 
involving a masters-level social worker working with inner-city children with asthma resulted in reduced asthma 
symptoms and was most cost-saving in those with more severe asthma.72, 73 In summary, these efficacious 
activities are integrated into the PAI which we now implement, testing its effectiveness and cost-effectiveness.  
Patient navigators have been nurses,74 social workers,72, 73, 75 community health workers76; none used the 
recent college graduates that have been successful in our pilot studies (See D.1.4). Our PAs, accepted by both 
patients and providers, have demonstrated they can facilitate such communication.77  
B.6. Comparative effectiveness research (CER) allows dissemination and implementation of a 
patient-oriented intervention to the real-world.78-86 CER compares patient-oriented interventions to current 
care using intention to treat (ITT) analyses in settings representative of “real-world” care.79 Given the 
established efficacy of asthma management, CER is needed to assess its real-world effectiveness.86 CER 
accommodates demographically diverse patients with complex lives and comorbidities and uses patient-
centered outcomes, as in the proposed project. As recommended by a recent NHLBI workshop,85 stakeholders 
were engaged in the design of this project through focus groups of patients and providers (D.1.3). Along the 
multi-faceted continuum from efficacy to CER, our proposal uses a pragmatic trial design,79, 86 a variety of 
outcomes important to its stakeholders (patients and providers),85, 87 and assesses the cost-effectiveness of the 
intervention in an RCT.88, 89 Literacy-sensitive disease management and addressing racial and ethnic 
disparities, themes of our proposal, are advocated as high priority in CER by the IOM and NIH.90-92 
B.7. Adherence, according to an IOM report,1 is a measure of the effectiveness of patient-provider 
communication; poor adherence is hypothesized to be an important mediator of minority status and poorer 
health and the result of unsatisfactory communication.1 In asthma, regular use of inhaled corticosteroids, 
reduces morbidity and mortality,93-99 and is recommended for all but those with the mildest disease. Poor 
adherence is presumed to be an important cause of asthma morbidity.100-103 Underuse occurs in all patient 
groups,104 even when medications are provided.105-108 Reasons include personal-level factors like fear of side 
effects, not believing in their benefit, or dissatisfaction with medical advice.108, 109 System-level deterrents 
include difficulty with access (cost, obtaining refills). Electronically recorded inhaled steroid use is the best 
measure of adherence in this setting,105, 110, 111 but is associated with a Hawthorne effect (Change in behavior 
due to known observation).77 Additionally, monitoring is not “real-world.” Thus, patient-centered outcomes: 
asthma control, ED visits, hospitalizations will be captured as primary outcomes. Adherence to inhaled 
steroids, explored as a mediator, will be self-reported, which correlates with monitored adherence.112 In 
addition, related to adherence, we will measure keeping of appointments with participant’s asthma provider.   
B.8. Our Conceptual Model (Fig 2) is based on the multilevel framework of Canino et al4 (Fig. 1) and 
hypothesizes that the PAI will improve asthma management measured by patient-centered outcomes: asthma 
control, prednisone bursts, ED visits, hospitalizations. Within the setting of preparing for, accompanying, and 
reviewing information and assignments after a medical visit, the PA will improve communication by coaching 
and modeling ways to ask questions, obtain information, communicate lack of understanding of medical 
information to providers. We hypothesize as a secondary analysis that the PAI will improve outcomes by 
improving patient self-efficacy, appointment-keeping, patient satisfaction with communication with the provider, 
adherence, and navigating ability. The PAI-health outcome relationship may vary depending upon different 
levels of moderators like educational attainment, and baseline health literacy, sociodemographics, 
comorbidities, community factors, presence of anxiety of depression, and clinician characteristics.113 Our model 
is grounded in Social Cognitive Theory (SCT) that suggests that individuals will engage in a behavior like 
asthma self-management to the degree they believe that they are capable of carrying it out to achieve a 
desired result, e.g. improved asthma control.114-117 SCT proposes that behavior and the environment (e.g. 
clinical practice, health system, social) interact continuously and these interactions should be taken into  

account.118 The individualized PAI does this. 
Because implementation of a PAI requires 
additional resources (time and personnel), we 
will estimate the incremental cost-
effectiveness of the PAI relative to usual care 
to help ascertain whether the additional 
resources are partially or completely offset by 
other savings, such as a reduction in asthma 
hospitalizations and ED visits.   
C. INNOVATION: Adults with moderate or 
severe asthma particularly those living in 
poverty are at risk for poor asthma outcomes. 
They often have comorbidities and 
community and social barriers that make 
accessing healthcare difficult, and frequently 
have had limited educational opportunities; all 
of which contribute to difficulties navigating 
the complicated health system and its practices. In addition, providers with limited time allotted to patients have 
little opportunity to understand these barriers and patients’ priorities. Such patients experience more 
hospitalizations and ED visits and shorter life spans. The PAI is innovative as a multi-faceted real-world 
intervention. The PAs, recent college-graduates without specific medical training but representative of the 
racial/ethnic diversity of the patients, are attractive to patients and the clinical practices alike. Because they do 
not require medical expertise, their tasks could potentially and ultimately be distributed to several members of 
one practice or across practices to those patients most in need. The protocol is innovative and significant for    
1) focusing on inner-city low-income predominantly minority adults who experience high asthma morbidity, 2) 
comparing the effectiveness of a PA to usual care in an implementation and dissemination format, 3) using a 
real-world behavioral intervention tested for sustainability in a RCT design, 4) testing a multi-faceted 
individualized intervention which considers comorbidities as it provides a model of chronic asthma 
management and is thus applicable to patients with other chronic diseases and comorbidities, 5) examining 
patient-provider communication, 6) using a unique PA, 7) using patient-centered outcomes including asthma 
control and ED visits, 8) carrying out the intervention in a variety of primary care and asthma specialty 
practices to improve generalizability, 8) includes Spanish- in addition to English-speaking patients, and 9) 
assessing the cost-effectiveness of PAI relative to UC. By considering mediators, moderators, and cost-
effectiveness, we provide a rich implementation design that will inform future comparative effectiveness 
research of both PAIs and other interventions among low-income urban populations. 
D. APPROACH 
D.1. Two studies, WIN and ongoing HAP, motivate, inform, and support PAI’s likelihood of success.77 These 
and other studies30, 52, 105, 108, 119-121 demonstrate our ability to recruit patients from low income urban 
neighborhoods with moderate or severe asthma and follow them for significant periods of time. All pertain to 
the patient-MD relationship beginning with a study of adherence which the IOM1 and our studies found to be a 
measure of the success of the patient-physician relationship.105, 108, 109  
D.1.1. WIN Study: “Individualized Interventions to Improve Adherence in Asthma” (R01 HL073932; 
Apter, PI),77 a randomized controlled trial (RCT), compared problem-solving (PS) to asthma education (AE) to 
improve inhaled steroid adherence and asthma outcomes in adults with moderate or severe asthma recruited 
from clinics serving low-income urban neighborhoods.52, 77, 121 PS involves identifying specific barriers to 
adherence, proposing and weighing solutions, trying the best, assessing, and revising. Adherence was 
monitored electronically.122 333 adults (English- or Spanish-speaking) were randomized: 49+14 years, 72% 
female, 68% African American, 7% Latino, mean FEV1 66%+19%, 52% with ED visits, 31% with 
hospitalizations for asthma in the prior year. Comorbidities were common: hypertension in 52%, diabetes in 
22%, mean BMI 33+9. In an intention to treat (ITT) analysis, there was no difference between groups with 
respect to overall change in any outcome (p>0.20). Mean adherence was 61% + 27%. Both groups changed 
similarly from baseline: adherence declined overall by 12% but asthma control,123 asthma-related quality of life 
(AQOL), and FEV1 improved overall by 15%, 18%, and 6% respectively. ED visits and hospitalizations did not 
significantly decrease. While PS was not better than AE, monitoring adherence with provision of medications 
and attention to patients given to both groups was associated with improvement in some asthma outcomes. 
Electronic monitoring is not a real-world intervention. Changes in inhaler formulation will make current monitors 
obsolete. Thus, monitoring is unlikely to be a feasible or cost-effective intervention.  
A secondary analysis: Exposure to community violence (ECV).52 In a longitudinal analysis we asked 
subjects whether they had witnessed violence in their neighborhood over the 6 months prior to enrollment. 
ECV was common, occurring in 23% and associated with 2.5 (95%CI: 1.1, 5.6) times more asthma-related 
hospitalizations, 2.3 (95%CI: 1.3, 3.9) times more ED visits for asthma, 1.7(95%CI: 1.1, 2.6) times more ED 
Patient Advocate 
Intervention
(PAI)
Figure 2. PAI is a real-world intervention to improve asthma management
Notes
*Primary outcome is Asthma Control
Comorbidities are treated as potential 
confounders.
AQOL= asthma-related quality of life
Mediators of PAI:
Self-efficacy
Appointment-keeping
Adherence
Satisfaction with communication
Navigating ability
Moderators
Educational attainment
Baseline Health literacy
Sociodemographics
Comorbidities
Community factors
Anxiety/Depression
Clinician characteristics
Health Outcomes
Asthma control*
Prednisone bursts
ED visits 
Hospitalizations
FEV1
AQOL

visits for any cause, and lower AQOL (-.40; 95%CI: -.77, -0.025) over the observation period. These results 
suggest that ECV generates psychosocial distress that directly affects health and/or is a marker for other 
physical/social exposures that contribute to poor outcomes, like the presence of environmental pollutants, 
inadequate housing, limited access to pharmacies and grocery stores, and poor public transportation. While a 
PAI may not be able to remedy these exposures, a PA may facilitate transfer of information so that the clinician 
can take account of such barriers to asthma management. 
Conclusions: The WIN Study demonstrated that an individualized intervention is feasible and acceptable. 
Monitoring, providing medications, and attention, the intervention in both groups, improved self-management to 
some degree but ED visits and hospitalizations did not significantly decrease, possibly because these had 
other determinants from social, community, and health access barriers. WIN did not take account of the 
practice environment. A real-world individualized intervention is needed that considers the patient, practice, 
providers, and social and community barriers impeding access to health care.  
D.1.2. “Literacy and improving patient-clinician encounters for asthma,” (K02 HL088469; Apter, PI), 
is ongoing research examining whether limited health literacy, particularly numerical skills, hinders patient-
physician communication and ultimately the ability to successfully self-manage asthma. We previously 
developed and validated the Asthma Numeracy Questionnaire (ANQ), a 4-item questionnaire derived from 
numerical concepts commonly used in patient instructions for self-managing asthma.119 ANQ scores indicated 
many adults do not understand the numerical concepts embedded in standard asthma education. Low ANQ 
scores were associated with hospitalizations and ED visits for asthma.119 We hypothesized that adequate 
literacy is associated with better health, mediated by patient-provider communication. We proposed a 
hierarchical model of numerical and communication skills to guide such communication.41  
The K02 Specific Aims test in participants of the parent WIN Study whether electronically-monitored 
inhaled steroid adherence, and asthma outcomes differ by literacy status. To the ongoing WIN Study, we 
added assessment of numeracy (ANQ) and reading comprehension, the Short Test of Functional Health 
Literacy in Adults (S-TOFHLA)124 to baseline questionnaires. In an analysis of the first 80 WIN participants for 
which we had literacy data, we found only 20% could answer all 4 ANQ items correctly.30 Less than half 
understood a question involving percentage (See Appendix, ANQ questionnaire, item 2). However, the reading 
comprehension score on the Short Test of Functional Health Literacy in Adults (S-TOFHLA)124 was adequate 
for 80% of participants. The ANQ results demonstrated that this test can distinguish among literacy levels.125 
Additionally, higher ANQ scores were associated with better AQOL and self-efficacy to accomplish asthma 
self-management.30 The association of numeracy and AQOL supports a link between literacy and health.  
 Preliminary analyses of the entire dataset for this analysis (n=284) adjusting for age, sex, race/ethnicity 
and the randomized intervention condition of WIN (PS vs AE), found that better adherence was associated with 
better numeracy (β = 2.70, 95% CI=[0.31, 5.10]) and reading comprehension (β =10.17, 95% CI=[1.48, 18.9]). 
Similarly, higher AQOL was associated with better numeracy (β =0.14 [0.02, 0.26]) and reading 
comprehension (β =0.63 [0.18, 1.07]). Asthma control was associated with reading comprehension (β =0.53 
[0.18, 0.88]). In summary, these findings support the need for an intervention directed at health literacy and 
communication as a pragmatic way of overcoming health disparities and improving asthma control.   
Conclusions: Numerical concepts in patient education may be difficult for patients to understand. Low 
literacy, reading and numeracy, is associated with poorer health outcomes. A PAI that facilitates 
communication with health care personnel about health information may be able to improve asthma outcomes. 
These preliminary analyses support our proposed secondary aims assessing potential mediators such as self-
efficacy and adherence, of the relationship between PA intervention and asthma control.  
D.1.3. Focus groups: To develop a feasible acceptable PAI, we conducted 4 focus groups of patients who 
completed the WIN Study and 2 of providers.121 Providers and patients thought a PA feasible and potentially 
beneficial, particularly as a means of social support. Providers thought PAs can help with tasks for which 
providers are limited by time, staff, or resources, such as helping with obtaining medications, transportation, 
insurance coverage, and medical information. Patients wanted an advocate (a term they preferred to 
“navigator”): “someone on your side.” They reported being anxious about medical visits, forgetting to ask 
questions and obtain prescriptions, and forgetting what the doctor said after they left the visit. Patients strongly 
recommended the PA be like the research coordinator (RC) of the WIN Study who they recognized as an 
advocate, uniformly preferring an RC to a community PA, possibly because they perceived the RC as accepted 
by and comfortable with clinical staff. The focus groups revealed that patients experienced a variety of barriers 
in addition to limited literacy (e.g., transportation difficulties, caring for sick family members, inability to afford 
co-payments or to obtain insurance), suggesting a resource book (see Appendix) and input from someone 
familiar with these resources, a PA, would be valuable.  
Conclusions: The PAI is acceptable to patients and providers. Patients’ need for instrumental social 
support and providers’ need to transmit medical information can be facilitated by the PA. 
D.1.4. The ongoing HAP Study: “A Patient Advocate & Literacy-Based Treatment of Asthma” (RC1 
HL099612; Apter, PI) demonstrates the feasibility of the PAI and compares it to standard asthma education 
(AE). Participants are adults with moderate or severe asthma (D.3), whose demographics and comorbidities 
are similar to WIN. Those in the PAI arm work with a non-health-professional PA who assists with and models 

preparations for a visit with the asthma doctor; attends visits; and afterwards confirms patient understanding, 
facilitating scheduling, obtaining insurance coverage, and overcoming other barriers to carrying out medical 
advice. The PA accompanies participants to 1-3 medical visits as scheduled by their asthma physician during 
the 16-week participation period. Electronically-monitored inhaled steroid adherence is the primary outcome; 
asthma outcomes also are obtained. Of 100 participants (100% of planned enrollment) 93 completed the 
protocol. Of 7 failing to finish, 3 had been assigned to the PAI and 4 to AE. Three withdrew being too busy, 
with school/job; 4 were lost to follow-up. A PA attended 65 medical appointments. One patient refused to have 
PA accompaniment to one medical visit. One physician refused to have the PA participate in one patient visit.  
Protocol refinements were made. To ensure adequate contact between PA and participant before a 
medical visit, we added brief PA visits following early data collection visits. Because we found the data 
collector (DC) received information from participants that might be useful to the PA, we modified the IRB 
consent to allow the DC and PA to journal about their contacts with participants in a blog accessible only to 
team members. A resource book of social services was developed. We discovered that we recruited asthmatic 
adults with high prevalence of low literacy and significant asthma morbidity, high rates of ED visits and 
hospitalizations. Highly educated patients with demanding highly paid jobs were too busy to enroll.  
Preliminary analysis of the 53 PA patients showed improvement in asthma control (decrease asthma 
control score from 2.23 to 1.67, p= 0.018126, 127) and asthma-related quality of life (3.75 to 4.34 p=-.001.128, 129 
(In both, a 0.5 change is clinically significant in an individual). FEV1 improved over 16 weeks from 65% to 69%, 
p=.25, but not significantly. These statistics provide preliminary evidence of the PAI’s efficacy. There was no 
difference between PA and AE groups, but the comparison was different from what we propose here. In HAP 
both groups were monitored, supplying a Hawthorne effect, there was not a usual care comparison, the study 
period was short only 16 weeks, and the study was underpowered for comparisons. Analyzing WIN data during 
this time, we realized monitored adherence is itself an intervention and so could not be an outcome for the 
proposed pragmatic intervention. Thus, usual care is a real-world comparison group. 
 Conclusions: The PAI intervention is acceptable, feasible, and shows evidence of efficacy. HAP and WIN 
taught us that UC is the appropriate comparison group.86   
D.2. Methods and Procedures 
D.2.1. Summary: This pragmatic RCT will recruit 300 adults with moderate or severe asthma from clinics 
serving low-income inner-city neighborhoods, randomizing participants 1:1, stratified by practice, to PAI or 
usual care (UC) for 6 months of intervention followed by 6 months of observation. We will assess PAI’s cost-
effectiveness. Secondary aims will assess mediators and moderators of the PAI-asthma outcome relationship. 
We will explore the awareness and response to PAI with post-study focus groups of providers. 
D.2.2. Design and Methodological Choices 
Design: We choose a RCT because randomization reduces the likelihood of bias from both known and 
unknown confounders.130 This is particularly important in a study of health behavior where many complex 
influences are not well understood, but will be equally distributed across comparison groups.  
Along the multidimensional continuum of explanatory/efficacy to pragmatic/effectiveness designs, this 
study has strong pragmatic/effectiveness features.79, 81, 86, 131 These include comparison of the PA intervention 
to the existing standard of care practiced in both specialty and primary care. The study population enrolled will 
be demographically diverse with significant asthma morbidity and a range of co-morbidities, selected only on 
the basis of having moderate/severe asthma (patients with mild asthma do not require the resources of a 
PAI).79  Smokers, often excluded in efficacy trials, are included.86  Randomization should equally distribute 
smokers, other comorbidities, and relevant characteristics to PA or UC groups. We will recruit from 
heterogeneous practice settings (primary care, specialty; federally qualified health center, academic health 
center, Veterans Affairs Medical Center (VA)) and collect a broad range of patient-oriented outcomes: asthma 
control, ED visits, hospitalizations, prednisone requirements, quality of life.79, 81  If cost-effective, the 
intervention can be implemented in a variety of settings.79 No special strategies will be used to improve study 
protocol adherence and the protocol is individualized.79 The analysis is ITT. The NIH and AHRQ have identified 
both pragmatic designs and achieving health equity as major priorities.82, 85, 91, 132 
Randomization by participant stratified by practice: The PAI is directed at the patient-PA interaction, so 
there is little opportunity for the providers to change their behavior with patients not randomized to PA. There 
has been no evidence of contamination of study arms in HAP. Randomization by clinic requires approximately 
20 sites; a multi-site trial is not feasible given the resources. We will convene post-study focus groups of 
providers to explore their awareness of the intervention and response to it. We will insert a post-study question 
for all participants (PAI and UC) asking if providers changed behavior during the study. 
Eligible consenting patient participants will be randomized 1:1 to PAI or UC.  Block randomization with 
block sizes ranging randomly between 4 and 6 consecutive participants within each site will be employed to 
ensure that equal numbers of participants are assigned to each of the two groups and are balanced with 
respect to observed and unmeasured baseline factors.133 Randomization will be single-blind; study 
investigators will be blinded to group assignment throughout the study and its analysis. Dr. Morales, the 
biostatistician, will generate randomization lists based on the above procedure. 

Participants are adults recruited from clinics serving low-income neighborhoods. Most asthma 
studies involve children; adults are relatively understudied. With the WIN and HAP Studies, we established 
effective recruitment methods and relationships with a variety of clinical practices to recruit and retain adults. 
Our experience suggests we will recruit patients with significant numbers of hospitalizations and ED visits and 
other health care costs. An effective intervention will reduce these costs and improve patient health. From 
HAP, we observed that patients who find a PA most useful will enroll. Very busy, employed, highly educated 
persons, least likely to benefit from a PA, do not have time to participate and do not enroll.  
PA activities: Informed by focus groups (D.1.3)121 and HAP (D.1.4), the PA will facilitate and model 
administrative tasks to navigate the health system and practice, prepare for visits, carry out medical 
recommendations, and overcome social and community barriers to accessing care. The PA will coach patients 
to articulate appointment goals and concern about or lack of understanding of medical advice. We will 
individualize PA activities surrounding 1) preparation for asthma doctor visits, 2) medical visits attended by the 
PA, and 3) ensuring understanding, scheduling, and administrative tasks agreed upon by doctor and patient.134   
Research coordinators (RCs) will function either as PAs or data collectors (DCs). PAs will not collect 
data; DCs will not perform PA activities. In our focus groups,121 patient participants preferred PAs to be like the 
RCs of the WIN study: recent college graduates interested in health-related or education careers, research 
experience, further schooling, working with patients, and generally having the same race/ethnicity distribution 
as potential subjects. We considered other choices: lay health workers, social workers,75 and nurses; but no 
one background has been shown to be superior.135 Ultimately, we followed the recommendation of our focus 
group participants. End of study questions and comments to DCs and PAs in the HAP study, collected from 
their blogs, confirmed participants like working with PAs and frequently ask to continue working with them 
when the study ends. HAP PAs were also well-received by clinic personnel. Since PAs do not take part in 
medical decision-making, they do not need extensive medical background. RCs will be thoroughly trained in 
asthma education, research principles, protocol integrity, and cultural competence (D.6.6). Training procedures 
will be derived from those already developed for the HAP Study.  
A resource for accessing social services: The WIN Study and the focus groups underscored the 
importance of knowledge of resources for overcoming insurance, social, and health system-related barriers. 
Heather Black, PhD has experience in provision of social services for disadvantaged populations in 
Philadelphia. She identified resources specific to the needs of asthma patients and developed a resource 
manual for HAP which we have updated (Appendix). She will review with the PA problems being encountered 
by participants pertaining to insurance, practice procedures, health system barriers that interfere with patients’ 
communication with their providers and their practices, and self-management of asthma.   
Comparison group: UC participants, like intervention participants will receive asthma care from their 
providers in the participating practices which generally follow asthma guidelines.103, 136 Data will be collected 
quarterly (q 3 months) to minimize a Hawthorne effect. We will not provide medications to either group.           
The Primary outcome is asthma control, patient-oriented and the primary therapeutic goal emphasized 
by national and international guidelines for managing asthma87, 137, 138 and a recent Asthma Outcomes 
Workshop.139 Preliminary data from the HAP Study demonstrates overall improvement in asthma control 
(D.1.4). Other asthma-related patient-oriented outcomes: prednisone bursts, ED visits, hospitalizations, ICU 
admissions, and quality of life (D.8.1) will be collected.139, 140 
 In WIN and HAP Studies, electronically-monitored adherence to inhaled steroids was the primary 
outcome. In WIN, both groups improved and the monitoring process was a common intervention between 
problem-solving and asthma education groups. Monitoring had 3 elements that together improved asthma 
outcomes: attention, monitoring feedback, and provision of inhaled steroids necessary for electronic 
monitoring. Thus, although adherence is a measure of patient-provider communication,1 it is not an appropriate 
outcome to test the effectiveness of this pragmatic PAI. Additionally, monitored adherence is not patient-
oriented or pragmatic. We will measure self-report of adherence, which is correlated to monitored adherence112 
and more pragmatic although less precise (D.8.2).  
Mediators and moderators: Potential mediators, testing how the PAI might affect asthma outcomes, were 
chosen from the literature and our preliminary results (B.8, Fig 2).113, 141-143 Self-efficacy, a prominent construct 
in social cognitive theory, is the conviction that one can successfully manage asthma.114-116 Specifically, we will 
measure self-efficacy as 1) confidence in filling out medical forms and 2) confidence in adherence to essential 
inhaled steroid regimens. Appointment-keeping and adherence to inhaled steroid regimens are measures of a 
working alliance between participant and provider facilitated by the PA. They are manifestations of self-
management and should lead to improved asthma outcomes.144-146 We hypothesize patient satisfaction with 
communication with providers should improve with the PAI. Finally, we have developed and are validating a 
questionnaire, Navigating Ability (Appendix) that measures specific participant beliefs and behaviors promoted 
by the PA. This validation study will be completed before the start of enrollment. Moderators are baseline 
characteristics that interact with PAI to influence the level of outcomes.113, 141 We will test whether the 
relationship between PAI and outcome changes across levels of a moderator,113, 141 including both patient 
(baseline health literacy, educational attainment,30 comorbidities, smoking history, socio-demographics, 

Table 1.  Data Collection for Specific and Secondary Aims   
Measure 
Visit 1 Baseline 
Randomization 
Visit 2 
Week12 
Visit 3 
Week 24 
Visit 4 
Week 36 
Visit 5 
Week 48 
Mediators 
 
 
 
 
 
Self-efficacy 
x 
x 
x 
x 
x 
Appointment keeping 
x 
x 
x 
x 
x 
Adherence  
x 
x 
x 
x 
x 
Satisfaction with communication 
x 
x 
x 
x 
x 
Navigating ability 
x 
x 
x 
x 
x 
Moderators  
 
 
 
 
 
Educational attainment 
x 
 
 
 
 
Baseline health literacy (ANQ, S-TOFHLA) 
x 
 
 
 
 
Socio-demographics 
x 
 
 
 
 
Comorbidities* 
 
 
 
 
 
Community factors (ECV) 
x 
 
 
 
 
Affective State: Anxiety/Depression 
x 
 
 
 
 
Clinician characteristics  
x 
 
 
 
 
Participant Outcomes 
 
 
 
 
 
Asthma Control 
x 
x 
x 
x 
x 
Prednisone bursts, ED, hospitalizations  
x 
x 
x 
x 
x 
Asthma–Related Quality of Life (AQOL)  
x 
x 
x 
x 
x 
Spirometry (FEV1, FVC)) 
x 
x 
x 
x 
x 
*Comorbidities include diabetes, hypertension, obesity, cancer, smoking history, and other conditions as reported by participant and verified in the medical record. 
ANQ= Asthma Numeracy Questionnaire, S-TOHFLA= Short Test of Functional Health Literacy in Adults, ECV= Exposure to community violence.    
community barriers,47, 52anxiety,147, 148 depression147, 149) and provider characteristics (demographics, practice 
type, years in practice).(See D.8.2, D.8.3, D.9)113   
Duration of patient participation in this pragmatic study is the longest observational period feasible 
based on HAP/WIN experiences: 12 months. For those in PAI, the intervention will take place in the first 6 
months. Both groups will be observed in the second 6 months without intervention. For both groups, number of 
visits  per 12 months with the asthma doctor will be recorded.   
Cost-effectiveness analysis: Implementation of a PAI will increase initial resource requirements. 
However, initial increased resource utilization may be partially or completely offset by savings related to better 
asthma outcomes, such as reductions in asthma-related hospitalizations and ED visits. Additionally, even if a 
PAI is not cost-saving, based on analysis of direct medical costs, it may be cost-effective from a societal 
perspective, which takes into account other non-medical and indirect benefits of improved asthma control, such 
as increased productivity and self-reported improvement in functional status and quality of life. 
D.3. Subjects: Inclusion criteria for 300 subjects (1-5 also of the HAP Study) are: 1) > 18 years of age, 2) 
physician’s diagnosis of asthma, 3) prescribed an inhaled-steroid-containing medication for asthma (ensuring 
the patient is believed to have moderate or severe reversible airways obstruction by their physician), 4) 
moderate or severe persistent asthma according to the NHLBI Guidelines,103 5) evidence of reversible airflow 
obstruction: (a) forced expiratory volume in 1 second (FEV1) < 80% predicted at the time of screening or within 
the 3 years prior to this screening, and (b) improvement with bronchodilator: either (i) an increase of >15% and 
200ml in FEV1 with asthma treatment over the previous 3 years or (ii) after 4 puffs of albuterol by MDI (or 2.5 
mg by nebulizer), an increase in FEV1 or FVC >12% and 200 ml in FEV1 within 30 minutes,103, 150 and 6) at 
least one appointment scheduled with the asthma physician during the 1st 6 months of participation.  
Exclusion criteria: 1) Severe psychiatric or cognitive problems (e.g., obvious mania, schizophrenia, 
significant mental retardation) that make it impossible to understand and carryout PA activities. Formal 
psychiatric evaluations are outside the scope of this project. However, RCs will be trained to identify patients 
during screening who do not appear to be mentally competent to carry out study tasks. Individual cases will be 
reviewed by the PI. In HAP and WIN Studies this has happened in 1-2 instances/study. Each clinical site has 
mental health facilities for referral of patients. 2) Unable to understand and provide informed consent, 3) 
Unable to communicate in English or Spanish. 4) Participants of the HAP Study are excluded.  
We will not exclude patients with other comorbidities who meet the above inclusion criteria. Patients with  
comorbidities may benefit most from a PA. Smoking is not an exclusion criterion. Initially, we excluded smokers 
in WIN, but eliminated this exclusion because it excluded significant numbers of patients, particularly poor 
patients, who might benefit from the intervention. Although this is a study of asthma patients, the PAI is not 
necessarily specific to asthma. Thus, defining “pure” asthma, if it were possible, is unnecessary.  

D.4. Recruitment sites include primary care and asthma-specialty practices in a variety of settings. There 
are 2 family medicine, 2 general internal medicine, 2 pulmonary and 1 allergy outpatient practice from the 
University of Pennsylvania Health System; practices at the Philadelphia Veterans Affairs Medical Center; the 
community-based primary care practice of the Woodland Avenue Health Clinic, a federally qualified health 
center; and the Episcopal Hospital Comprehensive Health Center, a primary care practice serving mainly 
Spanish-speaking patients. All sites have a large pool of patients with asthma and serve urban low income and 
minority patients from the surrounding communities. We have previously recruited from all sites. Having 10 
sites, including both specialty and primary care practices, improves the generalizability of the results by asthma 
severity and patient demographics and ensures adequate enrollment. Eight sites are within walking distance of 
our office and the last two are easily accessed by public transportation (See Resources). All participating 
practices will have an orientation meeting prior to the beginning of recruitment.  
D.5. Recruitment procedures: As for the HAP Study, the RC will screen electronic or paper health 
records for patients with upcoming appointments in participating practices who have an asthma diagnosis and 
are prescribed an inhaled-steroid-containing medication. Data collectors (DCs) will call or approach potential 
participants at the practice and request consent for further screening. IRB-approved consent (See Human 
Subjects) will be read in English or Spanish as appropriate to the potential participant to permit screening. A 
second consent will be obtained for enrollment. Recruitment will be continuous. Seasonal variation in asthma 
will be controlled by randomization and by recruiting through all seasons.  
D.6. Protocol  
D.6.1. Data Collection Visits generally occur at a private location in the practice of the participant’s 
asthma provider. (Most providers are physicians; but some are physician trainees (residents, fellows), or nurse 
practitioners.) After explanation of the protocol, informed consent is obtained and baseline data collected by 
the DC (Table 1, Fig. 2)). Participants then are randomized (D.2.2) 1:1 to either PAI or UC. As a pragmatic trial, 
there is no run-in as this would select those most adherent.79 Except for the test of reading comprehension, 
questionnaires are read to patients as they look on in English or Spanish as preferred by the participant. All 
questionnaires and all scripts have been translated into Spanish and independently reviewed by other native 
Spanish speakers and compared with English versions. Data collection (Table 1) occurs quarterly. All 
participants are reminded of data collection appointments with a phone call a few days prior to the visit.  
At each visit the DC asks participants how they are feeling and about urgent care obtained since the last 
visit, e.g., ED visits, hospitalizations, new or increased prednisone prescriptions (“prednisone bursts”). From 
HAP we know there will be 3-5 participant visits with the clinician during the observation period for both PA and 
UC participants. PA, but not UC, activities surround these visits. Randomization ensures approximately equal 
numbers of MD visits (which will be tallied) in participants assigned to PA and UC. 
  
D.6.2. PA protocol: As in HAP, the PA meets the PA-assigned participant after randomization at Visit 1. 
After introductions, the PA gives the participant some personal background (e.g., where the PA grew up, went 
to school, career goals) to begin to establish the PA-patient relationship and to motivate the patient to 
volunteer similar information. The PA gives the participant a notebook containing pages to enter medications; a 
calendar for appointments; and a page to enter contact information for physicians, pharmacies, and insurance 
(Appendix). It contains a sample action plan that the PA encourages the patient to discuss with their asthma 
doctor. This notebook is used at subsequent meetings with the PA and as the patient otherwise desires. At 
Visit 2 the PA again meets briefly (5 minutes) with the patient following data collection to further solidify the PA-
patient relationship. They may review clinician recommendations or converse about personal experiences or 
plans. In HAP we found it was important for the patient to get to know the PA as much as possible before the 
medical visits. The PA meets the participant before, during, and after a visit to the asthma-treating clinician and 
models, facilitates, and empowers patients to complete tasks related to asthma management. Activities before 
during and after visits were prompted by our focus groups.121   
  
A few days before each visit with the asthma clinician: By phone or in person, the PA assists the 
participant in making a medication list to provide to the MD, if not already made. Patient and PA discuss any 
problems with obtaining, refilling, or taking medications. The participant reviews any questions she/he plans to 
address with the clinician, as this has been shown to improve communication and patient satisfaction with the 
visit.151 The PA prompts the patient to prepare no more than 2 to 3 points to address at the medical visit (We 
found preparing too many points to be frustrating to the clinician who may have other issues to discuss and to 
the patient if they are not addressed). The PA inquires if forms, referrals, or other documents are needed for 
the visit and helps the patient obtain them if necessary.  
 
The PA meets the patient in the waiting room when the patient comes for a visit. The PA asks the 
participant if there is an emergency plan for an exacerbation and encourages the participant to discuss this at 
the visit if it is not well described by the patient. The PA helps the participant organize any needed materials, 
e.g. study results, medication lists, insurance information in the notebook. The PA uses the waiting time (which 
is sometimes considerable) to get to know more about the patient’s life and priorities. 
During the Medical Visit: If participant and clinician permit, the PA accompanies the participant as an 
observer. In general the PA speaks only if invited by the participant.121 Patients and clinicians sign consent that 
allows PAs to take notes to assist with “teach back” (patient repeating provider recommendations). 

In primary care practices, other health issues besides asthma will likely be discussed. The PA will assist in 
organizing the visit to include all health issues and “teach back” to include all health recommendations. 
Immediately after the Medical Visit: As needed, the PA facilitates scheduling follow-up appointments with 
the clinician and/or others as recommended and completion of any paperwork, e.g., insurance forms or other 
documents. The PA reviews instructions given to the participant at the appointment by asking the patient to 
“teach back,” that is, to teach the instructions as if the patient were the clinician. If the participant has questions 
for the clinician after reviewing these instructions, the PA and participant complete a report of items needing 
clarification for the clinician or staff. Such reports have improved asthma outcomes and patient satisfaction.9 
The PA and participant, as necessary, organize medical and administrative information. 
Between Visits: If there has been no contact with a participant for a month, the PA calls, and checks how 
the patient is feeling, general well-being, and whether the patient has sufficient medications. They review 
upcoming appointments. The PA asks whether there are new problems surrounding obtaining care or obtaining 
or taking medications and whether there have been ED visits or hospitalizations. The participant with help as 
needed from the PA, will notify the clinician of problems judged significant by either PA or participant.   
The PA will make use of the social service resource book and Dr. Black as needed. With patient consent, 
PAs and DCs will keep a log of impressions and information given by patients that is shared only among team 
members. PA visits and the logs will be discussed at weekly team meetings to solve problems patients have in 
self-managing asthma. (For example, sometimes a patient shares important information with the DC, this 
mechanism allows the DC to forward it to the PA. If the DC or team is concerned that information impacts on 
participants’ health, the PI will be notified and, as she judges necessary, the medical service).  
D.6.3. UC protocol: There are no meetings with a PA; PAs do not accompany participants or play a role in 
doctor visits. There are phone calls as needed to schedule data collection visits. 
D.6.4. Participant honorarium: Potential participants receive $10 for screening. Participants receive a 
total of $170: $25 for each of data collection Visits 1–4, $70 for completing Visit 5. Public transportation tokens 
provided for all data collection visits. (No payment is given for PA visits or attending medical visits.)  
D.6.5. Participating providers will be informed about the project in a conference and by email prior to 
enrolling patients. The protocol will be described generally as a study comparing ways to improve asthma 
outcomes. Clinicians will be asked to complete a brief questionnaire of demographics, type of practice, years in 
practice, and on strategies used in accommodating patients with low literacy. Since current national guidelines 
for asthma87 recommend visits for moderate/severe asthma at 1-6 month intervals if control is not optimal (i.e. 
symptoms or bronchodilator response), we will ask if we may schedule all otherwise eligible participants for an 
appointment during study participation, if they had not been seen in the last 3 months and no appointment is 
scheduled. The HAP Study demonstrated that patients generally have upcoming clinician appointments and 
there is no difficulty ensuring participants have such a medical visit for asthma scheduled during participation. 
In that brief 16-week study of 53 patients assigned a PA, 36 patients had at least one visit, 20 had 2 visits, and 
9 had 3 visits with their asthma provider.  
Upon randomization to PAI, we will send a letter/email to the patient’s asthma doctor informing them of the 
enrollment and briefly describe protocol activities prior to and after a visit. The letter will ask permission, if the 
participant agrees, for the PA to accompany the participant to an appointment. We will not communicate with 
doctors of UC participants. Thus, a doctor will likely not know if a patient is enrolled in the UC arm. 
D.6.6. RC training and protocol integrity: RCs will train for 3 weeks initially, using procedure manuals of 
recruitment, protocol, and data collection adopted from HAP. Training topics include asthma pathophysiology 
and education; spirometry; human subjects research; cultural competence; interpersonal skills; relating to 
practice personnel; administrative tasks required of patients; procedures for reviewing medical records, 
screening, enrolling, obtaining consent, recognition of adverse and serious adverse events, and data collection 
procedures.152 Training will involve observation of encounters with participants by the project manager and 
review of procedures and problems at weekly team meetings with the PI. To ensure protocol integrity all 
sessions will be taped. A random sample of 10% of the sessions will be chosen for formal assessment of 
integrity by the PI. If a researcher believes a patient’s asthma or health is unstable, Dr. Apter and the patient’s 
clinician will be notified immediately. At least two RCs will be fluent in Spanish.  
D.7. Post-study focus groups of providers (Exploratory Aim): We will convene three 2-hour focus groups 
of 5-8 providers, with at least 3 providers whose patient had a PA and some providers who did not come in 
contact with a PA. Led by Heather Black, PhD, using methodology of our earlier focus groups,121 providers will 
be asked about their awareness of and response to PAs and how PAs might change practice procedures. (See 
Appendix for draft of script). Data will be collected by audio recording and note-takers. 
D.8. Measures are classified as predictors (PAI or UC), outcomes, mediators, and moderators (Fig 2, Table 1, 
See Appendix for questionnaires). All questionnaires have Spanish versions.   
D.8.1. Outcomes: The primary outcome, asthma control, reflecting symptoms over the past week, will be 
measured using the 7-item version of the Asthma Control Questionnaire (ACQ).123, 153, 154 The score is the 

Table 2: Project Timeline 
Year 
1 
2 
3 
4 
5 
Months 
1-6 
7-8 
9-12 
13-16 
17-20 
21-24 
25-28 
29-32 
33-36 
37-40 
41-44 
45-48 
49-52 
53-56 
56-60 
Start up: finalize 
IRB approval, 
finalize CRFs, 
train staff, create 
database 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
New enrollment 
 
50 
100 
100 
50 
 
 
 
 
 
Follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Focus groups: 
set up, conduct, 
analyze 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSMB meets 
X 
  
  
 
X
  
 
   
 
  
  
  
 
  
X 
  
the mean of all responses (0=total control, 6=extremely 
uncontrolled). The minimally important clinical 
difference is 0.5. A score >1.5 is considered 
inadequate control.155 Several other patient-oriented 
outcomes will be evaluated. AQOL will be measured 
with the Mini-Asthma Quality of Life Questionnaire 
(AQLQ).126, 128, 129 This 15-item questionnaire has a 7-
point response scale that provides a mean summary 
score. A 0.5-unit change is considered clinically 
meaningful.129 The AQLQ has been shown to be a 
useful indicator of AQOL in low-income adults.156 
Participants will report hospitalizations including ICU 
admissions, ED visits, urgent medical visits (scheduled 
< 24 hrs in advance), prednisone bursts (a new 
prescription for > 3 days of prednisone or an increase in an already-prescribed dose for an asthma 
exacerbation), and other medical visits. DCs will examine medical records for documentation. Spirometry will 
be obtained using American Thoracic Society procedures for FEV1 and FVC.150   
D.8.2. Mediators explain how the PAI could influence asthma outcomes (B.8, D.2.2).113 We will measure 
self-efficacy, appointment keeping, adherence to inhaled steroid regimens, satisfaction with communication 
with providers and practices, and ability to navigate the clinical practice/health system. Self-efficacy will be 
measured by response to “How confident are you filling out medical forms by yourself?”, a validated question 
that correlates with REALM, a standard test of literacy.157, 158 Subjects also will complete our previously 
validated questionnaire of self-efficacy that asks about confidence to take prescribed inhaled steroids 
regularly.105, 108, 159 Appointment-keeping will be assessed by reviewing administrative records to assess if 
appointments with the asthma provider are kept (appointments kept/appointments scheduled). We will 
measure adherence to inhaled steroids using the Inhaler Adherence Scale, a 6-item tool which we used in 
HAP and WIN.160 Its range is 0-6, a lower score associated with better adherence. In WIN this score correlated 
with monitored adherence (corr=.23, p=0.002). Patient satisfaction with patient-provider communication will be 
measured with our previously used 13- item questionnaire.105, 108 Each item has a 6-point response scale. The sum 
is used as the measure (alpha 0.74). We are validating a questionnaire, Navigating Ability, which focuses on 
specific tasks promoted in the PAI protocol (Appendix). The instrument was completed by a small number of 
patients (n=31); we observed a Cronbach’s alpha=0.54, potentially suggesting there are several concepts 
being measured by the instrument (i.e. multidimensional). We observed a trend towards a positive correlation 
of the overall score with numeracy (Spearman correlation=0.35, p-value=0.057), reading comprehension (0.30, 
p=0.098), and perception of benefits over risks of inhaled steroids (0.32, p=0.082). 
D.8.3. Moderators are baseline variables, gleaned from the literature, hypothesized to affect the PAI- 
outcomes relationships.113 They include patient educational attainment (years of formal education completed), 
household income, other socio-demographics, comorbidities (patient reported and verified in the medical 
record including hypertension, diabetes, obesity, cancer, smoking history, etc). Baseline health literacy will be 
measured with the Asthma Numeracy Questionnaire (ANQ), the brief 4-item questionnaire of numerical 
concepts (arithmetic, percentage) that we developed and validated.119 Reading comprehension will be tested 
using the Short Test of Functional Health Literacy in Adults (S-TOFHLA).124 Community barriers are estimated 
by measuring report of exposure to community violence (D.1.1).52  Social cognitive theory predicts anxiety 
inhibits learning. We will use the 20 trait items of the State-Trait Anxiety Inventory (C. Spielberger, Mind 
Garden, Inc).161 Depressive symptoms will be measured by the Center for Epidemiologic Studies Depression 
Scale, a validated 20-item scale.162 Clinician characteristics include demographics, years in practice, type of 
medical practice (primary care vs. specialty; physician vs. nurse-practitioner; resident vs. attending, etc).  
D.8.4. Costs: Direct medical costs of intervention administration will be measured by the resource-costing 
method.73, 163, 164 The primary resource used in the treatment intervention is PA time. Each contact, the type of 
contact, and the duration of the contact (including preparation, travel, waiting and follow-up time) will be 
recorded by the PA on a case report form initiated at the time of each contact. The cost of a contact per hour is 
based on PA wage plus a proportion of the fixed costs of training and of the facility. Other medical resources 
such as office visits, hospital, ED, MD urgent visits will be converted into costs based on insurance 
reimbursement rates. Drug use is recorded on the case report forms. The cost of medication will be estimated 
from US average wholesale prices published in the Red Book or actual insurance payments (including patient 
co-payments).163, 164 The total direct medical costs of treatment are the sum of all of these components. The 
perspective for the primary cost analysis will be that of the payer. We also will estimate direct medical costs 
and incremental cost-effectiveness attributable to the intervention from a societal perspective, including patient 
co-payments and indirect costs such as patient and family member time, lost/gained productivity etc. The base 
case analysis will value indirect costs using a standardized representative rate per unit time. Sensitivity 
analyses will estimate representative wage rates by job category for employed individuals and examine a 

range of representative rates for those not employed. We will adjust costs for inflation using the Consumer and 
Medical Price Indices, as appropriate, and discount costs to the base year using a discount rate of 3%.163, 164 
D.9. Data Analysis: We will perform descriptive analyses of all variables, then compare PA and UC groups for 
the adequacy of randomization, examining if covariates or baseline variables including potential moderators of 
the intervention and mediating relationships are equally distributed among patient groups. These baseline 
comparisons will be based on t-tests or Wilcoxon rank sum tests for continuous variables depending on the 
symmetry of the distributions, on logistic regression for binary or ordinal variables; and on Poisson log-linear 
regression for count data. If imbalances are found at baseline, the relevant variables will be treated as 
confounders in the ITT analyses and the analyses of mediators and moderators of the intervention on asthma 
control. To account for the potential for variation in the effectiveness of the intervention across physician 
practices, our analyses will compensate by including site as a fixed effect in all analyses. Analyses of PA and 
UC differences with respect to change from baseline at 6 and 12 months for each outcome in Aims 1 and 2 will 
be based on the ITT principle: all randomized subjects will be included in the analysis regardless of whether 
they drop out of the intervention or study. We will perform a sensitivity analysis of the missing at random 
assumption by following Bruce et al165 with a non-ignorable shared parameter model.166  
The analysis will be based on random effects (RE) models applied to baseline and all follow-up visits at 
which outcome data are collected. The RE will be included to account for correlated and missing data. 
Separate time effects and time-treatment interactions will be specified for each follow-up visit, such that the 
treatment-time interaction for a particular visit will be the ITT effect on change since baseline. The RE models 
will be linear, logistic, and log-linear for continuous, binary, and count outcomes, respectively. Similar RE 
models will be employed for assessment of mediation and moderation in Secondary Aims 1 and 2. 
Data description, screening, and reorganization: We will screen data for quality and integrity as 
proposed by Altman.167 For all variables we will determine measures of central tendency: mean and standard 
deviation for continuous variables, median and range for categorical variables. We will examine frequency 
distribution graphically (histograms, scatter plots) for all variables. Specific concerns will be directed to 
understanding the pattern of missing values, isolating outliers, confirming the homoscedasticity of observation 
groups, verifying the coding consistency, examining adherence to normality for variables anticipated to be so, 
and locating normalizing transformations for continuous variables intended to be investigated as such.  For the 
tools we developed, we will examine internal consistency using Cronbach’s α.  
Addressing the impact of site on each outcome: First, we will pool participants across sites, assuming 
no site effect, using logistic and regression modeling to isolate the relationship between outcome and exposure 
and other demographics. We have stratified randomization to analyze the effect of site. We have amplified the 
sample size (D.10) to have a large enough sample to conduct this analysis. As a secondary analysis, we will 
examine treatment-site interactions. In the presence of statistically significant interactions, we will present 
separate estimates of treatment effects for each site. In the case of statistically, but clinically marginally 
significant interactions, we will present main effect estimates of treatment effect but with interactions in the 
model using –1, 0, 1 dummy coding for site, so that the main effects’ estimates will be for the average site. 
Aims 1 & 2 (To assess whether PAI improves asthma control and other asthma outcomes): The ITT 
effect of PA relative to UC on change in asthma control and other asthma outcomes since baseline at 6 
months will be assessed with estimation and testing of the treatment-6 month visit interaction in the linear RE 
model (described above) with asthma control as the dependent variable. In addition, the treatment-12 month 
interaction will be tested and estimated to assess if the ITT effect is retained after the PA intervention ends. 
Secondary Aim 1 (Mediators): The mediation analysis will follow the 4-step regression approach for 
testing mediated effects of Holmbeck.113 First, we will examine the association between PAI and mediators 
(D.8.2) by fitting separate longitudinal RE models with each mediator as the dependent variable. These models 
will test the effects of the PAI relative to the UC group with respect to change since baseline at each follow-up 
visit for the potential mediators. Second we examine the association between the PAI and asthma control as 
described in Aim 1. Third, we will assess the relationship between the mediators and asthma control by fitting 
separate longitudinal RE models with the mediators (D.8.2) as the independent variables and asthma control 
as the dependent variable. Finally, the mediators with significant effects at steps 1 and 3 will be included as a 
lagged time-varying covariate in the ITT linear RE model for asthma control in Aim 1. Mediators of the PAI will 
be assessed by comparing the randomization (intervention) effect estimate with and without the potential 
mediator in the model. A reduction of at least 15% in the treatment-visit interaction parameters at 6 and 12 
months due to the inclusion of the mediator in the model will be the criteria for a significant mediator.130  
Secondary Aim 2: Moderators of the intervention (D.8.3) will be tested and estimated with 3- and 2-way 
interactions among the treatment factor, potential moderator, and visit factor in the ITT model in Aim 1. 
Similarly, moderators of the mediating relationship will be assessed with 3- and 2-way interactions among the 
treatment factor, mediator, potential moderator, and visit factor in the mediation model in Secondary Aim 1.  
Specific Aim 3 (To estimate the incremental costs and incremental cost-effectiveness (ICE) of PA): 
ICE will be assessed by comparing the incremental cost of PA (including both intervention costs, as well as 
costs of care) relative to UC per outcome, e.g. cost per day asthma control or avoided ED, hospitalization. The 
ICE will be determined based on differences in direct costs (payer perspective) and also including indirect 

costs (societal perspective) and will be calculated based on differences in mean costs for the UC group from 
those in the PA group, divided by the mean difference in outcomes (asthma control, prednisone bursts, ED 
visits, hospitalizations, etc.). We also will calculate the incremental cost per quality adjusted life year as 
estimated from the AQOL. We will estimate statistical error and construct confidence intervals using bootstrap 
procedures168 for the incremental cost difference and the incremental cost-effectiveness ratio (ICER). 
Exploratory Aim (Post-study focus groups of providers): Audio records and notes will be coded into 
categories emerging from the data by independent coders (A Apter, I Bennett, H Black) who will achieve inter-
coder reliability.169 Using the Grounded Theory approach,170 we will then analyze the agreed upon categories, 
and place them into themes emerging from discussions.   
D.10. Sample size: We will enroll 300 adults (150 per intervention group). The primary outcome (Aim 1) is 
asthma control at Visit 3 (6 months) and Visit 5 (12 months). While a clinically meaningful difference in asthma 
control within-individual is 0.5, we expect the average difference across groups to be smaller. The WIN Study 
demonstrated a small difference in mean change of 0.2+1.1 in asthma control across intervention groups at 
Visit 8 (6 months).77 The effect was neither clinically nor statistically significant. A difference in mean change of 
0.32 in asthma control was found in a study with a different focus,171 but the effect was not statistically 
significant, probably due to the small sample size.  
Specific Aim 1: The power analysis is based on the 2-sample t-test with adjustments for 3 or 5 repeated 
measures per participant. The adjustment for clustering by patient multiplies the estimated sample size under 
simple random sampling by a design effect, d=1+ρ(n-1), where n=average number of visits per patient, and ρ is 
the patient intraclass correlation. We apply a conservative intraclass correlation of 0.30. The power analysis 
also takes into consideration the following factors: 1) 18% drop-out as observed in WIN; 2) adjusted 2-sided 
significance level of 0.025; and 3) 80% power. With these factors, the study is powered to observe a 
standardized effect of 0.29 and 0.32 difference in mean change in asthma control across intervention groups at 
6 months and 12 months, respectively. Specific Aim 2: The power analysis examines the intervention effect 
on 5 asthma outcome measures at 6 and 12 months. Using the same assumptions but with 2-sided α=0.005 to 
conservatively adjust for multiple comparisons, we will have 80% power to detect a standardized effect of 0.34 
and 0.31 between groups at 6 months and 12 months, respectively. Specific Aim 3: Power for the economic 
analysis172, 173 (costs have greater variability than clinical outcomes) is 81% based on the same effect size, 2-
sided α of 0.05, an effect-cost correlation of -0.1, a difference in cost of $500 and a willingness to pay (WTP) 
threshold of $2500 per year of improved adherence or avoided hospitalization. An increase in the WTP to 
$3000 results in 98% power. Thus, the sample size will provide sufficient statistical power for assessment of 
both clinical and economic evaluations (which requires detecting both effect and cost differences).172, 173 
D.11. Data Management: The Clinical Research Computing Unit will collaborate to finalize CRFs, construct 
the database, protect its security, perform data entry, review, query and update data; assist with preparation of 
DSMB reports, and collaborate with biostatisticians as it has for HAP and WIN studies. 
D.12. The Data Safety Monitoring Board (see Human Subjects) will meet at study start, year 2, and year 5. 
At these and every 6 months the DSMB will review reports of accrual, baseline comparability between PA and 
UC groups, adverse events, safety concerns, data quality, maintenance of confidentiality and recommend 
study modifications and whether the study can continue.  
D.13. Timeline is summarized in Table 2. Some staff is already identified and trained. We have established 
relationships at recruitment sites and successful recruitment strategies. The MOP of HAP needs minor 
modifications. HAP case report forms require small modifications.   
D.14. Anticipated problems:  Insuring recruitment/retention: We will use our successful procedures, using 
electronic medical records, and relationships developed with practices. We obtain contact information, e.g., cell 
phone, address, for 3 contacts per participant. Incentives will be given for each DC Visit with the largest at the 
final visit. We flexibly accommodate meeting times for the convenience of participants. RCs will be diverse, 
reflecting participant demographics. Guaranteeing a culturally appropriate intervention: RCs will undergo 
formal training. Co-investigators are also diverse and will in observation of the protocol and in staff meetings 
guarantee a culturally appropriate approach. Standardizing delivery of PA will be accomplished by the use of 
procedure manuals; standardized, well-annotated, and carefully constructed case report forms; regular direct 
observation; and audio-taping of researcher interactions with participants. Assuring physicians do not treat UC 
participants like PA participants: Physicians will not know which of their patients, if any, are enrolled in the UC 
arm, only those in PA. Almost all of the intervention takes place between PA and patient or is PA-related so it 
is unlikely to result in change of provider behavior in the absence of a PA. DCs will ask all subjects post-study 
if they noted changes in their physician over the study period. Post-study focus groups should add support to 
this claim. Differences in the impact of the intervention between specialty and primary care practices: will be 
explored in post-intervention focus groups and in the quantitative analysis of outcomes and mediators.  
D.15. Summary: This RCT disseminates and implements the PAI to improve asthma outcomes in primary care 
and specialty practices, in an academic health center, a federally qualified health center, a VA and in English- 
and Spanish-speaking practices, testing its effectiveness, sustainability, and cost-effectiveness. The real-world 
individualized PAI is compared to usual care, crafted for a vulnerable population, considers patients’ unique 
contexts, social barriers, and comorbidities and is generalizable to many diseases and medical settings.   

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