Gastrointestinal biopsies and amyotrophic lateral sclerosis – results from a cohort study of 1.1 million individuals

Figures & data

Table 1 Characteristics of cohort participants.

	Individuals with a gastrointestinal biopsy result of normal mucosa	Matched individuals to individuals with a gastrointestinal biopsy result of normal mucosa	Individuals with a gastrointestinal biopsy result of non-specific inflammation	Matched individuals to individuals with a gastrointestinal biopsy result of non-specific inflammation
N	483,442	2,392,647	566,663	2,724,515
Age at cohort entry (Mean ± SD), years^a	44.44 ± 20.40	44.33 ± 20.38	50.82 ± 21.83	50.25 ± 21.80
<60, n(%)	360,430 (74.55)	1,789,874 (74.81)	339,415 (59.9)	1,671,948 (61.37)
≥60, n(%)	123,012 (25.45)	602,773 (25.19)	227,248 (40.1)	1,052,567 (38.63)
Gender, n(%)
Male	184,065 (38.07)	912,794 (38.15)	277,558 (48.98)	1,338,643 (49.13)
Female	299,377 (61.93)	1,479,853 (61.85)	289,105 (51.02)	1,385,872 (50.87)
Total follow-up years	4,821,138	27,284,849	5,245,783	33,179,029
Mean follow-up years (Mean ± SD)	9.97 ± 7.99	11.40 ± 8.09	9.26 ± 8.38	12.18 ± 8.59

SD: standard deviation.

a Cohort entry: date of first biopsy record for individuals with a gastrointestinal biopsy result of normal mucosa or non-specific inflammation, and date of selection for the matched individuals without any gastrointestinal biopsy.

Table 2 Hazard ratios (HRs) and 95% confidence intervals (CIs) of amyotrophic lateral sclerosis (ALS) among individuals with a gastrointestinal (GI) biopsy result of normal mucosa, compared to matched individuals without any gastrointestinal biopsy.

		Main analysis		Sensitivity analysis 1		Sensitivity analysis 2
Characteristics	Group	Cases of ALS/person-years	HR (95%CI)	Cases of ALS/person-years	HR (95%CI)	Cases of ALS/person-years	HR (95%CI)
Entire cohort	No biopsy	1069/22,036,228	1.00(Reference)	983/19,961,016	1.00(Reference)	910/18,026,803	1.00(Reference)
	Normal mucosa	251/4,389,549	1.22(1.04–1.42)	222/3,908,813	1.24(1.05–1.46)	201/3,472,418	1.24(1.04–1.47)
	Upper GI	167/2,729,473	1.25(1.04–1.50)	145/2,446,118	1.24(1.02–1.51)	129/2,185,983	1.22(0.99–1.50)
	Lower GI	84/1,660,076	1.15(0.89–1.49)	77/1,462,695	1.23(0.94–1.61)	72/1,286,435	1.28(0.97–1.70)
Male	No biopsy	491/8,303,883	1.00(Reference)	448/7,516,374	1.00(Reference)	412/6,783,532	1.00(Reference)
	Normal mucosa	107/1,545,253	1.20(0.94–1.51)	95/1,377,629	1.26(0.99–1.62)	82/1,225,585	1.23(0.94–1.60)
	Upper GI	78/962,132	1.32(1.01–1.74)	70/864,776	1.43(1.07–1.90)	61/775,442	1.37(1.01–1.86)
	Lower GI	29/583,120	0.94(0.61–1.45)	25/512,853	0.94(0.59–1.49)	21/450,143	0.93(0.56–1.54)
Female	No biopsy	578/13,732,345	1.00(Reference)	535/12,444,641	1.00(Reference)	498/11,243,271	1.00(Reference)
	Normal mucosa	144/2,844,296	1.23(1.01–1.50)	127/2,531,184	1.22(0.99–1.51)	119/2,246,833	1.24(1.00–1.55)
	Upper GI	89/1,767,340	1.19(0.93–1.53)	75/1,581,342	1.11(0.85–1.45)	68/1,410,540	1.11(0.84–1.47)
	Lower GI	55/1,076,955	1.30(0.94–1.79)	52/949,842	1.43(1.02–2.00)	51/836,293	1.50(1.07–2.11)
<60 years*	No biopsy	566/17,742,581	1.00(Reference)	514/15,942,748	1.00(Reference)	464/14,280,182	1.00(Reference)
	Normal mucosa	119/3,538,078	1.17(0.94–1.44)	104/3,131,628	1.17(0.93–1.47)	95/2,765,930	1.19(0.94–1.52)
	Upper GI	83/2,201,204	1.22(0.94–1.57)	72/1,958,642	1.20(0.91–1.57)	65/1,737,412	1.20(0.90–1.60)
	Lower GI	36/1,336,874	1.06(0.73–1.55)	32/1,172,986	1.11(0.74–1.65)	30/1,028,518	1.17(0.77–1.78)
≥60 years*	No biopsy	503/4,293,647	1.00(Reference)	469/4,018,267	1.00(Reference)	446/3,746,621	1.00(Reference)
	Normal mucosa	132/851,471	1.24(0.99–1.56)	118/777,185	1.34(1.06–1.70)	106/706,488	1.26(0.98–1.61)
	Upper GI	84/528,269	1.22(0.92–1.60)	73/487,477	1.26(0.94–1.69)	64/448,571	1.15(0.84–1.57)
	Lower GI	48/323,202	1.29(0.88–1.87)	45/289,709	1.51(1.02–2.22)	42/257,917	1.48(0.99–2.21)

*Age at cohort entry.

Adjusted for age at cohort entry, sex, county of residence, and number of healthcare visits. In the main analysis, we excluded from the analysis the first 2 years after cohort entry. In the sensitivity analysis 1 and sensitivity analysis 2, we excluded from the analyses the first three or four years after cohort entry, respectively.

Table 3 Hazard ratios (HRs) and 95% confidence intervals (CIs) of amyotrophic lateral sclerosis (ALS) among individuals with a gastrointestinal (GI) biopsy result of non-specific inflammation, compared to matched individuals without any gastrointestinal biopsy.

		Main analysis		Sensitivity analysis 1		Sensitivity analysis 2
Characteristics	Group	Cases of ALS/person-years	HR (95%CI)	Cases of ALS/person-years	HR (95%CI)	Cases of ALS/person-years	HR (95%CI)
Entire cohort	No biopsy	1797/27,271,301	1.00(Reference)	1665/24,896,334	1.00(Reference)	1530/22,669,929	1.00(Reference)
	Non-specific inflammation	298/4,742,693	1.00(0.88–1.15)	263/4,240,574	0.97(0.84–1.12)	236/3,789,789	0.97(0.83–1.13)
	Upper GI	204/2,318,500	1.03(0.87–1.22)	181/2,057,460	1.00(0.84–1.20)	165/1,823,239	1.02(0.85–1.23)
	Lower GI	94/2,424,193	0.96(0.76–1.21)	82/2,183,114	0.91(0.71–1.17)	71/1,966,550	0.88(0.67–1.15)
Male	No biopsy	995/13,404,513	1.00(Reference)	935/12,240,779	1.00(Reference)	867/11,150,946	1.00(Reference)
	Non-specific inflammation	170/2,332,678	1.00(0.83–1.20)	152/2,089,188	0.96(0.79–1.17)	140/1,870,706	0.96(0.78–1.18)
	Upper GI	121/1,110,916	1.01(0.81–1.26)	108/986,762	0.98(0.78–1.23)	102/875,632	1.00(0.79–1.28)
	Lower GI	49/1,221,762	0.97(0.71–1.34)	44/1,102,426	0.93(0.66–1.30)	38/995,074	0.87(0.61–1.25)
Female	No biopsy	802/13,866,788	1.00(Reference)	730/12,655,555	1.00(Reference)	663/11,518,983	1.00(Reference)
	Non-specific inflammation	128/2,410,015	1.01(0.82–1.24)	111/2,151,386	0.98(0.78–1.22)	96/1,919,083	0.98(0.77–1.25)
	Upper GI	83/1,207,584	1.06(0.82–1.37)	73/1,070,698	1.03(0.78–1.36)	63/947,607	1.04(0.78–1.40)
	Lower GI	45/1,202,431	0.93(0.66–1.30)	38/1,080,688	0.88(0.61–1.28)	33/971,476	0.89(0.60–1.32)
<60 years*	No biopsy	738/19,263,325	1.00(Reference)	663/17,425,053	1.00(Reference)	617/15,713,870	1.00(Reference)
	Non-specific inflammation	104/3,287,225	0.98(0.78–1.22)	96/2,924,725	0.99(0.79–1.25)	85/2,600,046	0.97(0.76–1.23)
	Upper GI	60/1,294,778	0.96(0.72–1.28)	56/1,129,862	1.00(0.74–1.35)	49/982,864	1.01(0.73–1.40)
	Lower GI	44/1,992,446	1.00(0.72–1.40)	40/1,794,863	0.98(0.69–1.40)	36/1,617,181	0.91(0.63–1.32)
≥60 years*	No biopsy	1059/8,007,976	1.00(Reference)	1002/7,471,281	1.00(Reference)	913/6,956,058	1.00(Reference)
	Non-specific inflammation	194/1,455,468	1.01(0.84–1.21)	167/1,315,848	0.97(0.80–1.17)	151/1,189,743	1.01(0.82–1.24)
	Upper GI	144/1,023,721	1.03(0.83–1.27)	125/927,598	0.99(0.79–1.24)	116/840,374	1.04(0.82–1.32)
	Lower GI	50/431,747	0.98(0.70–1.37)	42/388,251	0.91(0.63–1.30)	35/349,369	0.92(0.62–1.37)

*Age at cohort entry.

Adjusted for age at cohort entry, sex, county of residence, and number of healthcare visits. In the main analysis, we excluded from the analysis the first 2 years after cohort entry. In the sensitivity analysis 1 and sensitivity analysis 2, we excluded from the analyses the first three or four years after cohort entry, respectively.

Figure 1 Kaplan-Meier plots of the probability of surviving patients relative to years since ALS diagnosis; Left figure, individuals with a biopsy result of normal mucosa (green dashed line) and their matched controls (p for log-rank test = 0.9768); Right figure, individuals with a biopsy result of non-specific inflammation (blue dashed line) and their matched controls (p for log-rank test = 0.9604).

Figure 2 Scatter plot of log2 transformed odds ratios (ORs) of gastrointestinal related diagnoses during the 5 years prior to the first biopsy (individuals with GI biopsy) or date of selection date (population controls). ORs were calculated from conditional logistic regression model, and p-values for all ORs were less than 0.05. Blue circles denote ORs that are greater for normal mucosa than non-specific inflammation. Green triangles denote ORs that are similar between normal mucosa and non-specific inflammation. Brown squares denote ORs that are smaller for normal mucosa than non-specific inflammation.

Data availability statement

Due to legal and ethical reasons, the data cannot be shared.