The Effectiveness of Actively Induced Medical Rehabilitation in Chronic Inflammatory Bowel Disease
Results from a randomized controlled trial (MERCED)
; ; ;
Background: The poor evidence base is a major problem for the German rehabilitation sector. This trial focused on testing the efficacy and benefit of inpatient medical rehabilitation compared to routine care in a single common entity, namely, chronic inflammatory bowel disease (IBD).
Methods: This pragmatic, multicenter, randomized controlled trial with a parallel group design included gainfully employed patients with IBD who were covered by one of four statutory health insurance providers. Patients in the intervention group were actively advised regarding options for rehabilitation and given support in applying for it; patients in the control group continued with the care they had been receiving before participation in the trial. The primary endpoint was social participation, and there were various secondary endpoints, including disease activity and sick days taken off from work. All parameters were assessed by questionnaire at the beginning of the trial and twelve months later. This was trial no. DRKS00009912 in the German clinical trials registry.
Results: In a complete case analysis, the intervention group (211 patients, of whom 112 underwent rehabilitation) did better than the control group (220 patients, of whom 15 underwent rehabilitation) in multiple respects. The reported limitation in social participation was reduced by 7.3 points in the intervention group and 2.9 points in the control group (p = 0.018; d = 0.23). Significant improvements were also seen in disease activity, vitality, health-related quality of life, and self-management, with effect sizes between 0.3 and 0.4. No benefit was seen in outcomes related to working capacity. Sensitivity analyses lent further support to the findings.
Conclusion: Rehabilitation research can be conducted with individually randomized, controlled trials. The findings of this trial indicate the absolute effectiveness of medically qualified rehabilitation for IBD patients, as well as its additional benefit compared to routine care.
Medical rehabilitation (MR) is a “service for participation.” In Germany, the DRV (Deutsche Rentenversicherung, German Pension Insurance) is its most important funding agency. The aim of MR is “to prevent impairment on the earning capacity of insured persons or early withdrawal from professional life or to integrate them in professional life as permanently as possible“ (section 9 subsection 1 of Book VI of the German Social Code [SGB VI]).A further aim of MR is to avert, eliminate, mitigate or compensate for and prevent progression of impairing chronic diseases (section 42 subsection 1, SGB IX).
Anyone wishing to participate in an MR program must submit an application themselves, which the attending physician accompanies with a form-based medical opinion. The DRV reviews whether certain medical and legal requirements are met. With an approval rate of 83%, the DRV funded about 832 936 inpatient MR services for adults in 2018 (1), including 3687 services for insured persons with chronic inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC). The mean rehabilitation duration was 23 days. The services were usually provided in specialized facilities located far away from the usual place of residence of the patient (2).
CD and UC belong to the group of disorders in which multiple areas are usually affected during periods of high disease activity (3). In addition to physical impairments, patients experience psychosocial problems, such as poor sex life, dietary restrictions, stress, or depression) (4). Such complex problems require an equally complex care approach. This is the strength of inpatient MR: It is provided by a multidisciplinary team, “all under one roof“. Besides medical specialists, the MR team comprises nursing staff, psychologists, physiotherapists, sports therapists, and occupational therapists, as well as nutritionists, social workers, and vocational counsellors.
The German system of inpatient MR is nearly unique; no other country has a directly comparable system in place (5). Thus, the increasing amount of data from studies conducted in other countries (6) does not do away with the question of the effectiveness and benefits of the German MR system. In 2014, the German Advisory Council on the Assessment of Developments in the Health Care System stated: “In conclusion, the lack of an evidence base is the core problem of the entire (national) rehabilitation sector. Studies on the absolute effectiveness of existing rehabilitation measures are lacking.“ (7)
In the following, we report results of a randomized controlled trial (MERCED study) evaluating the effectiveness of inpatient medical rehabilitation compared to the continuation of routine care close to where the patient lives (absolute effectiveness). Participants were working persons with chronic inflammatory bowel disease covered by social insurance. Since the study included a number of pension funds and health insurances as well as several rehabilitation clinics, statements on the general effectiveness of MR can be made. The study is based on a design that has been gradually optimized since 2006 (8, 9, 10, 11). It allows—to the best of our knowledge for the first time for this indication—to compare inpatient MR with the continuation of ongoing standard care. Our approach was pragmatic (12, 13) and—by involving a patient advisory board– also participatory (14).
The aim of the project is to reduce the deplored evidence deficit for an exemplary indication and, in doing so, contribute to the evidence base for MR in terms of methodology and content. At the same time, it is intended to demonstrate the repeatedly doubted feasibility of conducting a randomized controlled trial (RCT) on the absolute effectiveness of inpatient MR.
(For detailed information, please refer to the eMethods Section).
The study was funded by the German Research Foundation (reference no.: RA 314/13–1) and conducted as a pragmatic, multicenter, parallel group, randomized controlled trial with two points of measurement (T0, T1) at an interval of twelve months.
Inclusion criteria and recruitment
Working DRV-insured patients aged from 18 to 63 years, who were members of one of the four participating statutory health insurances, were included in this study. All of these patients had at least two reports of incapacity for work because of Crohn’s disease (ICD-10 K50) or ulcerative colitis (K51) in their health insurance billing data. Their respective health insurance mailed them the study information and invitation provided by us. Interested insured persons contacted the study administration in Lübeck which sent them detailed study information as well as a questionnaire to assure they met the inclusion criteria and to document the baseline situation. Invited persons were excluded if they lacked the subjective need for rehabilitation, if they lacked at least one complicating psychosocial problem (4), if they stated not being able to participate in a rehabilitation program in the near future, if they had undergone MR in the past 2 years, and if informed consent was not provided.
Randomization and rehabilitation application
The included insurees were 1:1 randomized to the two arms of the study. The intervention group (IG) was supported by the study administration in preparing the rehabilitation application with written material, access to an additional information website, and individual counseling by phone/email. Using their “option” (“Wunsch- und Wahlrecht” of section 9 SGB IX; the right to individual wishes and choice), they were asked to select one of the 7 rehabilitation facilities listed by the patient organization DCCV (Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung e. V., German Crohn’s Disease/Ulcerative Colitis Association). The standardized procedures for submitting a rehabilitation application, application review, application approval, and conduct of the rehabilitation program remained untouched.
The participants in the control group (CG) continued their previous treatment without any change. After the 12-month follow-up survey (T1), they received the study administration’s support offer.
Outcomes and measuring tools
The evaluation of the effectiveness of participation in medical rehabilitation was performed exclusively on the basis of patient-reported data from self-completion questionnaires. The primary outcome was the experienced limitation to participation in social life, measured using the index for measuring limitations in participation (IMET) (15, 16). Nine items are used to obtain data on limitations in various areas of everyday activities (including work, school, housework, leisure time, social relations) using numerical rating scales (0 = not impaired at all; 10 = completely impaired). The total score (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90) was calculated based on these ratings.
In order to cover a broad range of potential rehabilitation effects, a total of 12 secondary outcomes were included and analyzed (Table 1).
The primary analysis included all insured persons with data available for both points of measurement (complete case analysis, CCA). They were analyzed in the study arm to which they had been randomly allocated, regardless of their MR participation. Drop-out analyses were performed to estimate potential bias. A subgroup analysis compared IG participants who underwent an MR program during the study period with CG participants who did not undergo rehabilitation. During the sensitivity analysis for the primary outcome, data for all missing cases were imputed for an intention-to-treat (ITT) analysis, using various methods.
The significance level for the type 1 error was set at 5%. For the testing of the secondary outcomes, a Bonferroni correction was applied to adjust the significance level (24). For interval-scale outcomes, differences between T0 and T1 measurements were calculated for each participant and the mean differences (Δ T0−T1) between IG and CG were tested for significance using two-sided t-tests for independent samples. For nominal and ordinal data, the Chi-square test was used for significance testing. As effect sizes for continuous parameters, Cohen’s d was calculated, for dichotomous parameters odds ratios.
Patient advisory board
This participatory research project was supported by the patient organization DCCV e. V. and by an eight-member patient advisory board for the entire duration of the project. Its involvement ranged from stage 1 (consultation) to 3 (collaboration) of the 4-stage model described by Sweeney & Morgan (14); for example, the patient advisory board was involved in the selection of the outcomes.
Ethics Committee and registration
The study was approved by the Ethics Committee of the University of Lübeck (reference number 16–047 of 8 March 2016) and registered with the German Registry of Clinical Studies (DRKS00009912).
Of the 4359 insured persons informed about the study, 1144 requested detailed study information. 228 of the 758 insured persons willing to participate did not meet the inclusion criteria. 530 insured persons were included in the study and randomized to IG (268) or CG (262). The recruitment target was set at 300 patients in each study arm. Twelve months later, 431 study participants filled in the follow-up questionnaire. The drop-out rate for the interval between study inclusion and follow-up survey was 21.3% (57 of 268) and 16% (42 of 262) in the IG and the CG, respectively (p = 0.122) (Figure).
The baseline characteristics of the analysis group are listed in Table 2.
In a drop-out analysis, the 99 drop-outs were compared with the 431 patients who participated in the follow-up survey. Only for the parameter “disease duration,” a significant difference was found: The disease duration among the drop-outs was 3 years shorter on average (eTable 1).
Application advice and rehabilitation participation
All participants in the IG received the written information pack; in addition, 28% (59 of 211) also made use of the website. 43% (90 of 211) approached the study administration directly with questions about the application process, either by phone or email.
112 (53.1%) of the IG members reported to have undergone a rehabilitation program which had been conducted in 81% in one of the 7 recommended rehabilitation facilities. The MR was performed about 4 months (median) after the baseline survey (interquartile range: 3–6 months).
In the CG, 15 patients (6.8%) had undergone MR between T0 and T1.
Complete case analysis for primary and secondary outcomes
The complete case analysis (N = 431) showed statistically significant advantages for the primary outcome in the IG (Table 3): The experienced limitation in social participation was reduced in the IG by 7.3 (SD = 21.1), in the CG by 2.9 (SD = 17.3) points (p = 0.018); this corresponds to a small effect size of d = 0.23. A clinically relevant improvement by 10 points in the IMET was achieved by 43.8% and 32.1% in the IG and CG, respectively (p = 0.013). The statistically significant advantage in the primary outcome for the IG was confirmed by the additional ITT analysis (eMethods, eTable 2).
Likewise, in 6 of the 12 secondary outcomes, significant advantages for the IG were found after alpha-error adjustment (p-values ≤ 0.004). The largest effect size (d = 0.37) was demonstrated for disease activity (reduction in the GIBDI [German Inflammatory Bowel Disease Activity Index] by 1.4 and 0.3 points in the IG and CG, respectively; p<0.001); at the time of the follow-up survey, 51.2% and 36.1% of the patients were in remission in the IG and CG, respectively (GIBDI ≤ 3) (p = 0.002), including steroid-free remission: 41.1% versus 29.5% (p = 0.017). In 2 of the 3 documented self-management aspects, the IG showed greater improvements; similarly, the increase in vitality and health-related quality of life was more pronounced in the IG (effect sizes around 0.3). In the direct measurement of change at the time of the follow-up survey, 58% and 35% showed an improved health status in the IG and CG, respectively (p<0.001).
In the other secondary outcomes, differences between IG and CG were not significant, but more favorable developments were also apparent in the IG, also in terms of constructive attitudes, level of being informed, and mental stress. The differences in the work-related outcomes were non-significant and irrelevant from a social medicine perspective.
Subgroup analysis (rehabilitants in the IG versus non-rehabilitants in the CG)
In addition to the primary analysis, only rehabilitants of the IG (N = 112) were compared to the non-rehabilitants of the CG (N = 205). At baseline, the two groups did not differ from each other (eTable 3). The rehabilitants of the IG achieved significantly better scores with larger (up to medium) effect sizes in all primary outcomes as well as all secondary outcomes, with the exception of work-related outcomes (eTable 4).
Utilization of healthcare services outside the rehabilitation sector
Patients in the IG and CG provided information about the utilization of the outpatient and inpatient healthcare sector before and during the study. No differences were found with regard to the type and frequency of consultation with specialists, the use of various medications and the use of rehabilitative services at the place of residence (eTable 5).
MERCED evaluated the effectiveness of inpatient MR for working persons with statutory health insurance suffering from IBD who at that time stated that they were in need of rehabilitation and prepared to undergo rehabilitation. The pragmatically designed RCT had no influence on the procedures of the rehabilitation funding authorities and the rehabilitation clinics.
Our analyses suggest that inpatient MR for this indication is of general and absolute effectiveness and benefit. The hypothesis of its specific effectiveness is supported by the finding that there were no differences between IG and CG patients’ utilization of other medical services, neither before nor after MR.
In the complete case analysis, the primary outcome and most secondary outcomes showed significantly higher levels of improvement in the IG compared to the CG. The effect sizes achieved were in the smaller range. Clinically relevant improvement in social participation and steroid-free remission were significantly more frequently observed in the IG compared to the CG. The subgroup analysis comparing rehabilitants (IG) with non-rehabilitants (CG) found numerically larger effect sizes; this also indicates specific effectiveness. Neither of the two analyses showed significant advantages for the IG in terms of the strictly socio-medical outcome parameters (employment status, subjective employment prognosis, number of sick days taken off from work). This finding will have to be addressed in a separate publication. It should be noted that staying in or returning to work is not the sole purpose of DRV-financed MR (25). In patients with IBD, MR appears to be most effective in terms of clinical and psychosocial outcomes.
Our study shows that randomized controlled trials can be conducted to evaluate the absolute general effectiveness of MR—contrary to opinions expressed for decades (26, 27, 28). To this end, recruitment was carried out with full disclosure to the target persons before they submitted their application for rehabilitation. The EPRA study, which was carried out almost at the same time, used an alternative approach: It randomized asthma patients after their rehabilitation applications had been approved to either immediate or delayed start of rehabilitation (29). Due to strong rehabilitation preferences of the recruited patients, it can be assumed that such a waiting group design (30) only allows the evaluation of short-term effects of MR. The situation before submission of a rehabilitation application is different. Frequently, these IBD patients—and their physicians—express doubt about the effectiveness and sustainability of MR. By proactively approaching insured persons who had previously been selected by their health insurances and who continued to select themselves, participants were found who were prepared to postpone a rehabilitation application by one year.
Limitations and weaknesses of the MERCED study
In the MERCED study, the strategy of proactively approaching insured persons potentially in need of rehabilitation may have brought a patient group to MR which is not normally seen there. However, the fact that the patient population of the MERCED study is more similar in its characteristics to other samples recruited in rehabilitation clinics (31, 32) than to IBD samples from outpatient care (33, 34) supports the appropriateness of the approach (eTable 6). Only in the area of school education is there an obvious difference: The proportion of patients with lower school education (max. 9 years) is smaller in the MERCED study. This most likely reflects the structure of the persons insured by the recruiting health insurances (35).
In the period between T0 and T1, about 20% of the randomized insured persons were lost to follow-up; these were not included in our complete case analysis. While no evidence of bias was found in the drop-out analysis, such bias cannot be excluded. A further weakness lies in the lack of clinical confirmation of the diagnosis. Instead, two incapacity for work certificates with matching ICD coding in the health insurance data and the self-declaration of a medically confirmed IBD were required for inclusion.
In all cases, these were conditions and changes reported by the insured persons; health insurance data on incapacity for work were not available as originally planned.
For every participant, the second survey was conducted almost exactly twelve months after the first. The follow-up period after the end of medical rehabilitation, on the other hand, was not uniform in the IG. The median duration was 8 months (interquartile range: 6; 9). This is due to differences in the length of the interval between rehabilitation application and approval and start of rehabilitation.
Instead of the target of at least 60%, only 53% (112 of 211) of the IG patients participating until the end of the study completed a medical rehabilitation program (see Figure). It is therefore all the more remarkable that the analyses consistently indicated significant and relevant, albeit weak, advantages for the IG.
In summary, this pragmatic, randomized, standard care–controlled trial generated evidence on the effectiveness and additional benefit of inpatient MR in working persons with statutory health insurance suffering from IBD which we think is convincing. There is little doubt that the greater improvements observed in the IG can be attributed to MR. However, the mechanisms of action of this highly complex intervention cannot be determined with this study design. Also unanswered remains the question of the cost-effectiveness of MR. Further comparable studies on this and other indications should be conducted — including studies with controlled variation of the rehabilitation program.
We thank the statutory health insurances AOK-Nordost, BARMER, Novitas BKK, and TK as well as their insurees for their willingness to support this health services research project by participating in the study. Our thanks also go to the project and patient advisory boards for their helpful support of this study project.
Scientists who submit a methodologically useful analysis proposal may, after anonymization, be provided with individual participant data (including metadata) on which the results presented in this paper are based. Three months after publication, these data will be available for a period of 3 years. Interested researchers may contact the first author.
Conflict of interest statement
The authors declare that no conflicts of interest exist.
Manuscript received on 10 July 2019; revised version accepted on 28 November 2019
Translated from the original German by Ralf Thoene, MD.
Dr. phil. Angelika Hüppe
Institut für Sozialmedizin und Epidemiologie
Universität zu Lübeck
Ratzeburger Allee 160
Cite this as:
Hüppe A, Langbrandtner J, Lill C, Raspe H: The effectiveness of actively induced medical rehabilitation in chronic inflammatory bowel disease—results from a randomized controlled trial (MERCED).
Dtsch Arztebl Int 2020; 117: 89–96. DOI: 10.3238/arztebl.2020.0089
For eReferences please refer to:
eMethods Section, eTables:
Dr. phil. Angelika Hüppe, Dr. human biol. Jana Langbrandtner, Cassandra Lill M.A.
Center for Population Medicine and Health Services Research, University of Lübeck:
Prof. Dr. med. Dr. phil. Heiner Raspe
|1.||Deutsche Rentenversicherung (eds.): Statistik der DRV. Rehabilitation 2018. Band 216. Berlin: Deutsche Rentenversicherung Bund 2019.|
|2.||Deutsche Rentenversicherung (eds.): Reha-Bericht 2018. Berlin: H. Heenemann GmbH & Co. KG 2018.|
|3.||Raspe H: Chronische Erkrankungen. Definition und Verständnis. Bundesgesundheitsbl 2011; 54: 4–8 CrossRef MEDLINE|
|4.||Hüppe A, Langbrandtner J, Raspe H: Komplexe psychosoziale Problemlagen bei Morbus Crohn und Colitis ulcerosa – Fragebogengestütztes Assessment als erster Schritt zur Aktivierung von Patientinnen und Patienten. Z Gastroenterol 2013; 51: 257–70 CrossRef MEDLINE|
|5.||Mittag O, Welti F: Medizinische Rehabilitation im europäischen Vergleich und Auswirkungen des europäischen Rechts auf die deutsche Rehabilitation. Bundesgesundheitsbl 2017; 60: 378–85 CrossRef MEDLINE|
|6.||Negrini S, Levack W, Gimigliano F, Arienti C, Villafane JH, Kiekens C: The struggle for evidence in physical and rehabilitation medicine: publication rate of randomized controlled trials and systematic reviews is growing more than in other therapeutic fields. Am J Phys Med Rehabil 2019; 98: 258–65 CrossRef MEDLINE|
|7.||Sachverständigenrat (SVR) Gesundheitswesen (eds.): Bedarfsgerechte Versorgung – Perspektiven für ländliche Regionen und ausgewählte Leistungsbereiche. Bern: Hans Huber 2014 CrossRef|
|8.||Hüppe A, Glaser-Möller N, Raspe H: Trägerübergreifendes Projekt zur Früherkennung von Rehabilitationsbedarf bei Versicherten mit muskuloskelettalen Beschwerden durch Auswertung von Arbeitsunfähigkeitsdaten: Ergebnisse einer randomisierten, kontrollierten Evaluationsstudie. Gesundheitswesen 2006; 68: 347–56 CrossRef MEDLINE|
|9.||Hüppe A, Parow D, Raspe H: Wirksamkeit und Nutzen eines Screeningverfahrens zur Identifikation von rehabilitationsbedürftigen Personen mit Diabetes mellitus Typ 2: Eine randomisierte, kontrollierte Evaluationsstudie unter Versicherten der Hamburg Münchener Krankenkasse. Gesundheitswesen 2008; 70: 590–9 CrossRef MEDLINE|
|10.||Mittag O, Döbler A, Pollmann H, Farin-Glattacker E, Raspe H: Praktikabilität und Nutzen eines aktiven Screenings auf Rehabedarf mit anschließender schriftlicher Beratung zur Rehaantragstellung bei AOK-Versicherten im Disease-Management-Programm Diabetes Typ 2 (PARTID-Studie). Rehabilitation 2014; 53: 313–20 CrossRef MEDLINE|
|11.||Schlademann S, Hüppe A, Raspe H: Ergebnisse einer randomisierten kontrollierten Studie zur Akzeptanz und zu Outcomes einer Beratung auf stationäre medizinische Rehabilitation unter erwerbstätigen GKV-Versicherten mit rheumatoider Arthritis. Gesundheitswesen 2007; 69: 325–35 CrossRef MEDLINE|
|12.||Ford I, Norrie J: Pragmatic trials. N Engl J Med 2016; 375: 454–63 CrossRef MEDLINE|
|13.||Loudon K, Trewek S, Sullivan F, et al.: The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015; 350: h2147 CrossRef MEDLINE|
|14.||Kirschning S, Pimmer V, Matzat J, Brüggemann S, Buschmann-Steinhage R: Beteiligung Betroffener an der Forschung. Rehabilitation 2012; 51: 12–20 CrossRef MEDLINE|
|15.||Deck R: IMET. Index zur Messung von Einschränkungen der Teilhabe. In: Begel J, Wirtz M, Zwingmann C (eds.): Diagnostische Verfahren in der Rehabilitation. Göttingen: Hogrefe 2008; 372–4.|
|16.||Deck R, Walther A, Staupendahl A, Katalinic A: Einschränkung der Teilhabe in der Bevölkerung – Normdaten für den IMET auf der Basis eines Bevölkerungssurveys in Norddeutschland. Rehabilitation 2015; 54: 402–8 CrossRef MEDLINE|
|17.||Hüppe A, Langbrandtner J, Häuser W, Raspe H, Bokemeyer B: Validation of the „German Inflammatory Bowel Disease Activity Index (GIBDI)“: an instrument for patient-based disease activity assessment in Crohn‘s Disease and Ulcerative Colitis. Z Gastroenterol 2018; 56: 1267–75 CrossRef MEDLINE|
|18.||Schuler M, Musekamp G, Faller H, et al.: Assessment of proximal outcomes of self-management programs: translation and psychometric evaluation of a german version of the health education impact questionnaire (heiQ). Qual Life Res 2013; 22: 1391–403 MEDLINE MEDLINE|
|19.||Osborne RH, Elsworth GR, Whitfield K: The health education impact questionnaire (heiQ): an outcomes and evaluation measure for patient education and self-management interventions for people with chronic conditions. Patient Educ Couns 2007; 66: 192–201 CrossRef MEDLINE|
|20.||Löwe B, Wahl I, Rose M, et al.: A 4 item measure of depression and anxiety: validation and standardization of the Patient Health Questionnaire-4 (PHQ-4) in the general population. J Affect Disord 2010; 122: 86–95 CrossRef MEDLINE|
|21.||Morfeld M, Kirchberger I, Bullinger M: SF-36 Fragebogen zum Gesundheitszustand: deutsche Version des Short Form-36 Health Survey. Göttingen: Hogrefe 2011 CrossRef|
|22.||The EuroQol Group: EuroQol – a new facility for the measurement of health-related quality of life. Health Policy 1990; 16: 199–208 CrossRef|
|23.||Mittag O, Raspe H: Eine kurze Skala zur Messung der subjektiven Prognose der Erwerbstätigkeit: Ergebnisse einer Untersuchung an 4279 Mitgliedern der gesetzlichen Arbeiterrentenversicherung zu Reliabilität (Guttman-Skalierung) und Validität der Skala. Rehabilitation 2003; 42: 169–74 CrossRef MEDLINE|
|24.||Victor A, Elsäßer A, Hommel G, Blettner M: Judging a plethora of p-values: how to contend with the problem of multiple testing – part 10 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2010; 107: 50–6 VOLLTEXT|
|25.||Buschmann-Steinhage R, Brüggemann S: Veränderungstrends in der medizinischen Rehabilitation der gesetzlichen Rentenversicherung. Bundesgesundheitsbl – Gesundheitsforsch – Gesundheitsschutz 2011; 54: 404–10 CrossRef MEDLINE|
|26.||Beck M, Löffler H (eds.): Rehabilitation heute: die Rehastudie Baden. Karlsruhe: G. Braun 1984; 17.|
|27.||Gerdes N, Weidemann H, Jäckel WH (eds.): Die Protos-Studie. Ergebnisqualität stationärer Rehabilitation in 15 Kliniken. Darmstadt: Steinkopff 2000; 5 CrossRef|
|28.||Haaf HG: Reha-Erfolg – Ist die Reha überhaupt wirksam? In: Ergebnisqualität in der medizinischen Rehabilitation der Rentenversicherung. Berlin: DRV-Bund 2009; 33.|
|29.||Schultz K, Seidl H, Jelusic D et al.: Effectiveness of pulmonary rehabilitation for patients with asthma: study protocol of a randomized controlled trial (EPRA). BMC Pulm Med 2017; 17: 49 CrossRef MEDLINE PubMed Central|
|30.||Jäckel WH, Cziske R, Gerdes N, Jacobi E: Überprüfung der Wirksamkeit stationärer Rehabilitationsmaßnahmen bei Patienten mit chronischen Rückenschmerzen: eine prospektive, randomisierte, kontrollierte Studie. Rehabiltiation 1990; 29: 129–133.|
|31.||Hüppe A, Steimann G, Janotta M, et al.: Auf dem Prüfstand: stationäre medizinische Rehabilitation bei chronisch entzündlichen Darmerkrankungen. Rehabilitation 2016; 55: 248–55 CrossRef MEDLINE|
|32.||Reusch A, Weiland R, Gerlich C, et al.: Self-management education for rehabilitation inpatients suffering from inflammatory bowel disease: a cluster-randomized controlled trial. Health Educ Res 2016; 31: 782–91 CrossRef MEDLINE|
|33.||Hüppe A, Langbrandtner J, Raspe H: Inviting patients with inflammatory bowel disease to active involvement in their own care: a randomized controlled trial. Inflamm Bowel Dis 2014; 20: 1057–69 CrossRef MEDLINE|
|34.||Langbrandtner J, Hüppe A, Jessen P, et al.: Quality of care in inflammatory bowel disease: results of a prospective controlled cohort study in Germany (NETIBD). Clin Exp Gastroenterol 2017; 10: 215–27 CrossRef MEDLINE PubMed Central|
|35.||Hoffmann F, Koller D: Verschiedene Regionen, verschiedene Versichertenpopulationen? Soziodemografische und gesundheitsbezogene Unterschiede zwischen Krankenkassen. Gesundheitswesen 2017; 79: e1–e9 CrossRef MEDLINE|
|e1.||Deutsche Rentenversicherung: Leitlinien für die sozialmedizinische Begutachtung für Stoffwechsel und gastroenterologische Erkrankungen sowie Adipositas. 2011. https://deutsche-rentenversicherung.de/SharedDocs/Downloads/DE/Experten/infos_fuer_aerzte/begutachtung/leitlinien_rehabeduerftigkeit_stoffwechsel_langfassung_pdf.pdf?__blob=publicationFile&v=1 (last accessed on 12 November 2019).|
|e2.||Janke KH, Raible A, Bauer M, et al.: Questions on life satisfaction (FLZM) inflammatory bowel disease. Int J Colorectal Dis 2004; 19: 343–53 CrossRef MEDLINE|
|e3.||Ackermann H: BiAS für Windows. www.bias-online.de/ (last accessed on 12 November 2019).|
|e4.||Alshurafa M, Briel M, Akl EA, et al.: Inconsistent definitions for intention-to-treat in relation to missing outcome data: systematic review of the methods literature. PLoS One 2012; 7: e49163 CrossRef MEDLINE PubMed Central|
|e5.||Kabisch M, Ruckes C, Seibert-Grafe M, et al.: Randomized controlled trials: part 17 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2011; 108: 663–8 VOLLTEXT|
|e6.||Jakobsen JC, Gluud C, Wetterslev J, Winkel P: When and how should multiple imputation be used for handling missing data in randomised clinical trials – a practical guide with flowcharts. BMC Med Res Methodol 2017; 17: 162 CrossRef MEDLINE PubMed Central|
|e7.||Edgell SE, Noon SM: Effect of violation of normality on the t test of the correlation coefficient. Psychological Bulletin 1984; 95: 576–83 CrossRef|
|e8.||Bortz J, Schuster C: Statistik für Human und Sozialwissenschaftler. Berlin: Springer 2010 CrossRef|
|e9.||Lenhard W, Lenhard A: Calculation of effect sizes. www.psychometrica.de/effect_size.html (last accessed on 12 November 2019).|
|e10.||Norman GR, Sloan JA, Wyrwich KW: Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003; 41: 582–92 CrossRef CrossRef|
|e11.||Farin-Glattacker E, Kirschning S, Meyer T, Buschmann-Steinhage R: Partizipation an der Forschung – eine Matrix zur Orientierung. Stellungnahme des Ausschuss „Reha-Forschung“ der Deutschen Vereinigung für Rehabilitation (DVfR) und der Deutschen Gesellschaft für Rehabilitationswissenschaften (DGRW). https://www.dvfr.de/fileadmin/user_upload/DVfR/Downloads/Fachausschuesse/Forschung/Partizipation_an_der_Forschung_%E2%80%93_eine_Matrix_zur_Orientierung.pdf (last accessed on 12 November 2019).|