Debra L. Schutte
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Previous Organizations / Institutes
The organizations / institutes from the scholar's other articles in the past ten years
Research Subjects
Debra L. Schutte has a total of 104 co-authors. Here are the top co-authors by number of shared publications:
- Janet K. Williams
College of Nursing, The University of Iowa, Iowa City, IA
8 shared publications Ann Marie McCarthy
College of Nursing, The University of Iowa, Iowa City, IA, USA
3 shared publicationsBrian C. Schutte
Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA
3 shared publicationsDavid Reed
3 shared publications- Jane S. Paulsen
University of Wisconsin‐Madison, Madison, WI USA
3 shared publications Jeffrey C. Murray
College of Medicine, The University of Iowa, Iowa City, IA, USA
3 shared publications
Latest Publications
- 1 January 2023
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 16 (1) , 21-32
Perceived Hearing Impairment in a Rural Community
CoSAGE Community Advisory and Ethics Committee; Age-related hearing impairment yields many negative outcomes, including alterations in mental health, functional impairments, and decreased social engagement. The purpose of the current study was to examine perceived hearing impairment and its relationship with person-centered outcomes among adults in a rural community setting. A cross-sectional, descriptive correlational design was used. Survey packets of validated instruments were distributed following all weekend services at a rural community church; 72 completed surveys were returned (26% response rate). Descriptive and inferential statistics, including Spearman's rank correlations (rs), were used to address the study aims. Mean age of participants was 54 years (SD = 17 years), 58% were female, and 97% attended church regularly. Thirty-one percent of respondents reported moderate to severe hearing impairment. Perceived hearing impairment was associated with more depressive symptoms (rs = 0.24, p = 0.052), poorer attentional function (rs = −0.29, p = 0.016), and decreased quality of life in the mental health domain (rs = −0.21, p = 0.081). Findings expand evidence supporting the relationship between hearing and person-centered outcomes, including a functional measure of cognition. These results serve as a foundation for the design of a community-driven, church-based hearing health intervention. [Research in Gerontological Nursing, 16(1), 21–32.]
- 1 January 2023
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 16 (1) , 21-32
Perceived Hearing Impairment in a Rural Community
CoSAGE Community Advisory and Ethics Committee; Age-related hearing impairment yields many negative outcomes, including alterations in mental health, functional impairments, and decreased social engagement. The purpose of the current study was to examine perceived hearing impairment and its relationship with person-centered outcomes among adults in a rural community setting. A cross-sectional, descriptive correlational design was used. Survey packets of validated instruments were distributed following all weekend services at a rural community church; 72 completed surveys were returned (26% response rate). Descriptive and inferential statistics, including Spearman's rank correlations (rs), were used to address the study aims. Mean age of participants was 54 years (SD = 17 years), 58% were female, and 97% attended church regularly. Thirty-one percent of respondents reported moderate to severe hearing impairment. Perceived hearing impairment was associated with more depressive symptoms (rs = 0.24, p = 0.052), poorer attentional function (rs = −0.29, p = 0.016), and decreased quality of life in the mental health domain (rs = −0.21, p = 0.081). Findings expand evidence supporting the relationship between hearing and person-centered outcomes, including a functional measure of cognition. These results serve as a foundation for the design of a community-driven, church-based hearing health intervention. [Research in Gerontological Nursing, 16(1), 21–32.]
- 1 September 2022
- Published by Wolters Kluwer Health in Clinical Nurse Specialist
- Vol. 36 (5) , 249-253
Linking Hospitals to Communities Through Evidence-Based Practice
Evidence-based practice (EBP) and innovation are critical to quality and improved outcomes in the acute care setting and are often driven by bedside caregiver and clinical nurse specialist collaboration. Several EBP models and frameworks exist to guide these efforts. Although existing models do not preclude external evidence and community-based stakeholders, they largely do not explicitly connect the hospital-based effort to the community either. In our experience in facilitating EBP projects within an acute care hospital in the upper Midwest, we observed multiple situations in which nurse-led EBP projects intersected with the surrounding community in multiple phases of the project. The purpose of this article is to demonstrate an explicit connection between hospital-placed EBP processes and community/population health. To illustrate this assertion, 3 exemplars of nurse-driven, hospital-placed innovation are presented. Implications for practice and research are discussed.
- 1 September 2022
- Published by Wolters Kluwer Health in Clinical Nurse Specialist
- Vol. 36 (5) , 249-253
Linking Hospitals to Communities Through Evidence-Based Practice
Evidence-based practice (EBP) and innovation are critical to quality and improved outcomes in the acute care setting and are often driven by bedside caregiver and clinical nurse specialist collaboration. Several EBP models and frameworks exist to guide these efforts. Although existing models do not preclude external evidence and community-based stakeholders, they largely do not explicitly connect the hospital-based effort to the community either. In our experience in facilitating EBP projects within an acute care hospital in the upper Midwest, we observed multiple situations in which nurse-led EBP projects intersected with the surrounding community in multiple phases of the project. The purpose of this article is to demonstrate an explicit connection between hospital-placed EBP processes and community/population health. To illustrate this assertion, 3 exemplars of nurse-driven, hospital-placed innovation are presented. Implications for practice and research are discussed.
- 1 May 2021
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 14 (3) , 114-116
Designing and Testing Complex Nursing Interventions for Older Adults: Tapping the Tools of the Trade
- 1 May 2021
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 14 (3) , 114-116
Designing and Testing Complex Nursing Interventions for Older Adults: Tapping the Tools of the Trade
- 1 July 2020
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 13 (4) , 191-202
Genetic Predictors of Knee Pain in Persons With Mild to Moderate Osteoarthritis
The purpose of this study was to examine genetic variability and knee pain in persons with osteoarthritis (OA). Seventy-five participants with medial compartment knee OA were recruited from a large Midwestern tertiary care center. Participants exhibited a mean age of 56.3 years; females comprised 61% of the sample. Measures of pain included subjective pain intensity at rest and with movement, cutaneous mechanical sensation and pain testing, heat pain threshold, and pressure pain threshold. Seventy-four participants were genotyped for 25 genetic variants across 15 candidate genes for central or peripheral pain pathways. Analysis suggests a role for four genes ( EDNRA , COMT , BDRKB1 , and IL1B ) in several components of pain in persons with knee OA. The results from this study will help guide the development and evaluation of tailored strategies to decrease pain, improve function, and prevent the development of new chronic pain syndromes in older adults experiencing OA. [ Research in Gerontological Nursing, 13 (4), 191–202.]
- 1 July 2020
- Published by SLACK, Inc. in Research in Gerontological Nursing
- Vol. 13 (4) , 191-202
Genetic Predictors of Knee Pain in Persons With Mild to Moderate Osteoarthritis
The purpose of this study was to examine genetic variability and knee pain in persons with osteoarthritis (OA). Seventy-five participants with medial compartment knee OA were recruited from a large Midwestern tertiary care center. Participants exhibited a mean age of 56.3 years; females comprised 61% of the sample. Measures of pain included subjective pain intensity at rest and with movement, cutaneous mechanical sensation and pain testing, heat pain threshold, and pressure pain threshold. Seventy-four participants were genotyped for 25 genetic variants across 15 candidate genes for central or peripheral pain pathways. Analysis suggests a role for four genes ( EDNRA , COMT , BDRKB1 , and IL1B ) in several components of pain in persons with knee OA. The results from this study will help guide the development and evaluation of tailored strategies to decrease pain, improve function, and prevent the development of new chronic pain syndromes in older adults experiencing OA. [ Research in Gerontological Nursing, 13 (4), 191–202.]
- Open Access
- 1 March 2020
- Published by Elsevier in Mitochondrion
- Vol. 51, 62-67
Mitochondrial haplogroups and lifespan in a population isolate
- 1 March 2020
- Published by Elsevier in Mitochondrion
- Vol. 51, 62-67
Open AccessMitochondrial haplogroups and lifespan in a population isolate
- 29 October 2019
- Published by Wiley in European journal of pain
- Vol. 24 (2) , 398-412
Effects of genotype on TENS effectiveness in controlling knee pain in persons with mild to moderate osteoarthritis
Background: This study examined the extent to which genetic variability modifies Transcutaneous Electrical Nerve Stimulation (TENS) effectiveness in osteoarthritic knee pain.Methods: Seventy‐five participants with knee osteoarthritis were randomly assigned to either: (a) High‐frequency TENS, (b) Low‐frequency TENS or (c) Transient Placebo TENS. Pain measures were collected pre‐ and post‐treatment. Participants were genotyped on genes implicated in central or peripheral pain pathways: NGFB, NTRK1, EDNRA, EDNRB, EDN1, OPRM1, TAC1, TACR1, BDNF, BDKRB1, 5HTT, COMT, ESR2, IL6 and IL1B. Genetic association using linear regression modelling was performed separately for the transient placebo TENS subjects, and within the High‐frequency TENS + Low‐frequency TENS participants, including TENS level as a covariate.Results: In the placebo group, SNPs rs165599 (COMT) was significantly associated with an increased heat pain threshold (β = −1.87; p = .003) and rs6827096 (EDNRA) with an increased resting pain (β = 2.68; p = .001). Within the treatment groups, TENS effectiveness was reduced by the SNP rs6537485 (EDNRA) minor allele in relationship to mechanical sensation (β = 184.13; p = 5.5E−9). Individuals with the COMT rs4680 minor allele reported lowered pain at rest after TENS (β = −42.30; p = .001), with a higher magnitude of pain reduction (28 unit difference) in the low‐frequency TENS group compared to the high‐frequency TENS group (β = 28.37; p = .0004).Conclusions: EDNRA and COMT are implicated in osteoarthritic knee pain and provide a basis for tailoring TENS interventions according to individual characteristics.Significance: Findings from this study demonstrate that genetic variation within the COMT and EDNRA genes influences the effectiveness of TENS, a non‐pharmacologic pain‐reduction intervention, in the context of osteoarthritic knee pain. Evidence such as this may contribute to risk models that provide a clinically useful tool for personalizing TENS interventions according to individual characteristics in order to best control pain and maximize functional status.
- 29 October 2019
- Published by Wiley in European journal of pain
- Vol. 24 (2) , 398-412
Effects of genotype on TENS effectiveness in controlling knee pain in persons with mild to moderate osteoarthritis
Background: This study examined the extent to which genetic variability modifies Transcutaneous Electrical Nerve Stimulation (TENS) effectiveness in osteoarthritic knee pain.Methods: Seventy‐five participants with knee osteoarthritis were randomly assigned to either: (a) High‐frequency TENS, (b) Low‐frequency TENS or (c) Transient Placebo TENS. Pain measures were collected pre‐ and post‐treatment. Participants were genotyped on genes implicated in central or peripheral pain pathways: NGFB, NTRK1, EDNRA, EDNRB, EDN1, OPRM1, TAC1, TACR1, BDNF, BDKRB1, 5HTT, COMT, ESR2, IL6 and IL1B. Genetic association using linear regression modelling was performed separately for the transient placebo TENS subjects, and within the High‐frequency TENS + Low‐frequency TENS participants, including TENS level as a covariate.Results: In the placebo group, SNPs rs165599 (COMT) was significantly associated with an increased heat pain threshold (β = −1.87; p = .003) and rs6827096 (EDNRA) with an increased resting pain (β = 2.68; p = .001). Within the treatment groups, TENS effectiveness was reduced by the SNP rs6537485 (EDNRA) minor allele in relationship to mechanical sensation (β = 184.13; p = 5.5E−9). Individuals with the COMT rs4680 minor allele reported lowered pain at rest after TENS (β = −42.30; p = .001), with a higher magnitude of pain reduction (28 unit difference) in the low‐frequency TENS group compared to the high‐frequency TENS group (β = 28.37; p = .0004).Conclusions: EDNRA and COMT are implicated in osteoarthritic knee pain and provide a basis for tailoring TENS interventions according to individual characteristics.Significance: Findings from this study demonstrate that genetic variation within the COMT and EDNRA genes influences the effectiveness of TENS, a non‐pharmacologic pain‐reduction intervention, in the context of osteoarthritic knee pain. Evidence such as this may contribute to risk models that provide a clinically useful tool for personalizing TENS interventions according to individual characteristics in order to best control pain and maximize functional status.
- 1 February 2019
- Published by Wolters Kluwer Health in AJN, American Journal of Nursing
- Vol. 119 (2) , 44-51
A Nurse-Driven Oral Care Protocol to Reduce Hospital-Acquired Pneumonia
Purpose: The purpose of this evidence-based quality improvement (QI) project was to implement an oral care protocol in the adult in-patient care areas of a level 1 trauma hospital and to evaluate its impact on the incidence of hospital-acquired pneumonia (HAP). Methods: A standardized, evidence-based oral care protocol was implemented depending on the level of care required by each ventilated, at-risk, or short-term care patient. The QI project included the introduction of a new suction toothbrush kit for at-risk patients and, for short-term patients, a new short-term oral care kit that featured a more ergonomically appropriate toothbrush, a baking soda toothpaste, and an alcohol-free antiseptic mouthwash; the project also supported the continued use of the then current suction toothbrush kit for patients receiving mechanical ventilation. We examined medical records retrospectively and used International Classification of Diseases (ICD) 9 and ICD 10 codes for pneumonia not present on admission to determine the incidence of HAP, including nonventilator hospital-acquired pneumonia (NV-HAP) and ventilator-associated pneumonia (VAP), in two seven-month periods: the baseline and intervention periods. Both periods were in the same seven calendar months of two different years to control for seasonal differences in pneumonia rates. Documentation of oral care interventions were compared with oral care supply use reports to measure protocol adherence in the intervention group. Results: There were 202 patients in the baseline group and 215 in the intervention group. A χ2 analysis of NV-HAP incidence showed a statistically significant decrease in occurrences of NV-HAP from 52 in the baseline group to 26 in the intervention group (χ2 = 12.8, df = 1, P < 0.001). The number of patient deaths from NV-HAP also differed significantly between groups, with 20 in the baseline group and four in the intervention group (χ2 = 4.33, df = 1, P = 0.037). NV-HAP incidence per 1,000 discharges was calculated at 2.84 in the baseline group and 1.41 in the intervention group. Among patients on a ventilator, there were 56 ventilatorassociated events (VAEs) with 12 cases of VAP in the baseline group and 49 VAEs and three cases of VAP in the intervention group. Infection rates in the baseline group were calculated as 12.53 VAEs per 1,000 ventilator days and 2.87 cases of VAP per 1,000 ventilator days. The intervention group yielded a VAE rate of 14.29 per 1,000 ventilator days and a VAP rate of 1.26 per 1,000 ventilator days. Overall, nurses' adherence to the new oral care protocol ranged from 36% to 100% per month, with an average adherence to protocol of 76% as evidenced by oral care documentation and supply use. Implications: Nurses improved pneumonia outcomes by providing oral health interventions to all adult patients admitted to the hospital, which reduced overall hospital costs, length of stay, and patient mortality.
- 1 February 2019
- Published by Wolters Kluwer Health in AJN, American Journal of Nursing
- Vol. 119 (2) , 44-51
A Nurse-Driven Oral Care Protocol to Reduce Hospital-Acquired Pneumonia
Purpose: The purpose of this evidence-based quality improvement (QI) project was to implement an oral care protocol in the adult in-patient care areas of a level 1 trauma hospital and to evaluate its impact on the incidence of hospital-acquired pneumonia (HAP). Methods: A standardized, evidence-based oral care protocol was implemented depending on the level of care required by each ventilated, at-risk, or short-term care patient. The QI project included the introduction of a new suction toothbrush kit for at-risk patients and, for short-term patients, a new short-term oral care kit that featured a more ergonomically appropriate toothbrush, a baking soda toothpaste, and an alcohol-free antiseptic mouthwash; the project also supported the continued use of the then current suction toothbrush kit for patients receiving mechanical ventilation. We examined medical records retrospectively and used International Classification of Diseases (ICD) 9 and ICD 10 codes for pneumonia not present on admission to determine the incidence of HAP, including nonventilator hospital-acquired pneumonia (NV-HAP) and ventilator-associated pneumonia (VAP), in two seven-month periods: the baseline and intervention periods. Both periods were in the same seven calendar months of two different years to control for seasonal differences in pneumonia rates. Documentation of oral care interventions were compared with oral care supply use reports to measure protocol adherence in the intervention group. Results: There were 202 patients in the baseline group and 215 in the intervention group. A χ2 analysis of NV-HAP incidence showed a statistically significant decrease in occurrences of NV-HAP from 52 in the baseline group to 26 in the intervention group (χ2 = 12.8, df = 1, P < 0.001). The number of patient deaths from NV-HAP also differed significantly between groups, with 20 in the baseline group and four in the intervention group (χ2 = 4.33, df = 1, P = 0.037). NV-HAP incidence per 1,000 discharges was calculated at 2.84 in the baseline group and 1.41 in the intervention group. Among patients on a ventilator, there were 56 ventilatorassociated events (VAEs) with 12 cases of VAP in the baseline group and 49 VAEs and three cases of VAP in the intervention group. Infection rates in the baseline group were calculated as 12.53 VAEs per 1,000 ventilator days and 2.87 cases of VAP per 1,000 ventilator days. The intervention group yielded a VAE rate of 14.29 per 1,000 ventilator days and a VAP rate of 1.26 per 1,000 ventilator days. Overall, nurses' adherence to the new oral care protocol ranged from 36% to 100% per month, with an average adherence to protocol of 76% as evidenced by oral care documentation and supply use. Implications: Nurses improved pneumonia outcomes by providing oral health interventions to all adult patients admitted to the hospital, which reduced overall hospital costs, length of stay, and patient mortality.
- Open Access
- 30 January 2019
- Published by SAGE Publications in Biological Research For Nursing
- Vol. 21 (2) , 157-165
Genetic Variants and the Cortisol Response in Children: An Exploratory Study
Objective: We examined genomic variation potentially associated with the cortisol stress response in children having a painful medical procedure. Design: Children 4–10 years old having a peripheral intravenous line inserted provided saliva samples for evaluation of the cortisol response as a biological measure of distress: two on the day of the procedure and two at home on a nonstressful day for comparison values. Children and biological parents also provided samples for genotyping of variants with known or suspected association with the cortisol stress response. Analysis included child-only association and family-based transmission disequilibrium tests (TDTs). Results: Genotype and phenotype data on the cortisol stress response were available from 326 children for child-only association analyses and 376 complete family trios for TDTs. Children were 50% female, an average of 7.5 years old, and mostly (83%) White/non-Hispanic. We identified four single-nucleotide polymorphisms (SNPs) potentially associated with the cortisol stress response: rs1176744 ( HTR3B), rs10062367 ( CRHBP), rs634479 ( OPRM1), and rs8030107 ( NTRK3). Family-based analysis identified a two-SNP haplotype in HTR1B suggestive for association with the cortisol response (rs6296, rs11568817). Allelic TDTs identified rs7897947 ( NFKB2) as potentially related to cortisol response. Conclusions: Findings provide preliminary evidence for genes potentially important in cortisol response to an acute stressor in children in the serotonin, dopamine, and brain-derived neurotrophic factor pathways, the hypothalamic–pituitary–adrenal axis, and the inflammatory response. Combined with analyses of related phenotypes and clinical data, these results could help identify patients at increased risk of adverse responses to painful medical procedures who might benefit from tailored interventions.
- 30 January 2019
- Published by SAGE Publications in Biological Research For Nursing
- Vol. 21 (2) , 157-165
Open AccessGenetic Variants and the Cortisol Response in Children: An Exploratory Study
Objective: We examined genomic variation potentially associated with the cortisol stress response in children having a painful medical procedure. Design: Children 4–10 years old having a peripheral intravenous line inserted provided saliva samples for evaluation of the cortisol response as a biological measure of distress: two on the day of the procedure and two at home on a nonstressful day for comparison values. Children and biological parents also provided samples for genotyping of variants with known or suspected association with the cortisol stress response. Analysis included child-only association and family-based transmission disequilibrium tests (TDTs). Results: Genotype and phenotype data on the cortisol stress response were available from 326 children for child-only association analyses and 376 complete family trios for TDTs. Children were 50% female, an average of 7.5 years old, and mostly (83%) White/non-Hispanic. We identified four single-nucleotide polymorphisms (SNPs) potentially associated with the cortisol stress response: rs1176744 ( HTR3B), rs10062367 ( CRHBP), rs634479 ( OPRM1), and rs8030107 ( NTRK3). Family-based analysis identified a two-SNP haplotype in HTR1B suggestive for association with the cortisol response (rs6296, rs11568817). Allelic TDTs identified rs7897947 ( NFKB2) as potentially related to cortisol response. Conclusions: Findings provide preliminary evidence for genes potentially important in cortisol response to an acute stressor in children in the serotonin, dopamine, and brain-derived neurotrophic factor pathways, the hypothalamic–pituitary–adrenal axis, and the inflammatory response. Combined with analyses of related phenotypes and clinical data, these results could help identify patients at increased risk of adverse responses to painful medical procedures who might benefit from tailored interventions.
- 13 March 2017
- Published by SAGE Publications in Biological Research For Nursing
- Vol. 19 (3) , 339-349
Relationship of Genetic Variants With Procedural Pain, Anxiety, and Distress in Children
This study used a candidate gene approach to examine genomic variation associated with pain, anxiety, and distress in children undergoing a medical procedure. Children aged 4–10 years having an IV catheter insertion were recruited from three Midwestern children’s hospitals. Self-report measures of pain, anxiety, and distress were obtained as well as an observed measure of distress. Samples were collected from children and biological parents for analysis of genomic variation. Genotyped variants had known or suspected association with phenotypes of interest. Analyses included child-only association and family-based transmission disequilibrium tests. Genotype and phenotype data were available from 828 children and 376 family trios. Children were 50% male, had a mean age of 7.2 years, and were 84% White/non-Hispanic. In family-based analysis, one single-nucleotide polymorphism (SNP; rs1143629, interleukin (IL1B) 1β) was associated with observed child distress at Bonferroni-corrected levels of significance (p = .00013), while two approached significance for association with high state anxiety (rs6330 Nerve Growth Factor, Beta Subunit, [NGFB]) and high trait anxiety (rs6265 brain-derived neurotrophic factor [BDNF]). In the child-only analysis, multiple SNPs showed nominal evidence of relationships with phenotypes of interest. rs6265 BDNF and rs2941026 cholecystokinin B receptor had possible relationships with trait anxiety in child-only and family-based analyses. Exploring genomic variation furthers our understanding of pain, anxiety, and distress and facilitates genomic screening to identify children at high risk of procedural pain, anxiety, and distress. Combined with clinical observations and knowledge, such explorations could help guide tailoring of interventions to limit procedure-related distress and identify genes and pathways of interest for future genotype–phenotype studies.
- 13 March 2017
- Published by SAGE Publications in Biological Research For Nursing
- Vol. 19 (3) , 339-349
Relationship of Genetic Variants With Procedural Pain, Anxiety, and Distress in Children
This study used a candidate gene approach to examine genomic variation associated with pain, anxiety, and distress in children undergoing a medical procedure. Children aged 4–10 years having an IV catheter insertion were recruited from three Midwestern children’s hospitals. Self-report measures of pain, anxiety, and distress were obtained as well as an observed measure of distress. Samples were collected from children and biological parents for analysis of genomic variation. Genotyped variants had known or suspected association with phenotypes of interest. Analyses included child-only association and family-based transmission disequilibrium tests. Genotype and phenotype data were available from 828 children and 376 family trios. Children were 50% male, had a mean age of 7.2 years, and were 84% White/non-Hispanic. In family-based analysis, one single-nucleotide polymorphism (SNP; rs1143629, interleukin (IL1B) 1β) was associated with observed child distress at Bonferroni-corrected levels of significance (p = .00013), while two approached significance for association with high state anxiety (rs6330 Nerve Growth Factor, Beta Subunit, [NGFB]) and high trait anxiety (rs6265 brain-derived neurotrophic factor [BDNF]). In the child-only analysis, multiple SNPs showed nominal evidence of relationships with phenotypes of interest. rs6265 BDNF and rs2941026 cholecystokinin B receptor had possible relationships with trait anxiety in child-only and family-based analyses. Exploring genomic variation furthers our understanding of pain, anxiety, and distress and facilitates genomic screening to identify children at high risk of procedural pain, anxiety, and distress. Combined with clinical observations and knowledge, such explorations could help guide tailoring of interventions to limit procedure-related distress and identify genes and pathways of interest for future genotype–phenotype studies.